Physiol Rev 98: 419 – 475, 2018

Published December 20, 2017; doi:10.1152/physrev.00043.2016

UNDERSTANDING KEY MECHANISMS OF

EXERCISE-INDUCED CARDIAC PROTECTION TO
MITIGATE DISEASE: CURRENT KNOWLEDGE AND
EMERGING CONCEPTS
Bianca C. Bernardo, Jenny Y. Y. Ooi, Kate L. Weeks, Natalie L. Patterson,
and Julie R. McMullen

Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne,
Victoria, Australia; Department of Diabetes, Central Clinical School, Monash University, Victoria, Australia;
Department of Medicine, Central Clinical School, Monash University, Victoria, Australia; and Department of
Physiology, School of Biomedical Sciences, Victoria, Australia

Bernardo BC, Ooi JYY, Weeks KL, Patterson NL, McMullen JR. Understanding

L
Key Mechanisms of Exercise-Induced Cardiac Protection to Mitigate Disease: Current
Knowledge and Emerging Concepts. Physiol Rev 98: 419 – 475, 2018. Published
December 20, 2017; doi:10.1152/physrev.00043.2016.—The benefits of exercise
on the heart are well recognized, and clinical studies have demonstrated that exercise
is an intervention that can improve cardiac function in heart failure patients. This has led to
significant research into understanding the key mechanisms responsible for exercise-induced
cardiac protection. Here, we summarize molecular mechanisms that regulate exercise-induced
cardiac myocyte growth and proliferation. We discuss in detail the effects of exercise on other
cardiac cells, organelles, and systems that have received less or little attention and require further
investigation. This includes cardiac excitation and contraction, mitochondrial adaptations, cellular
stress responses to promote survival (heat shock response, ubiquitin-proteasome system, au-
tophagy-lysosomal system, endoplasmic reticulum unfolded protein response, DNA damage re-
sponse), extracellular matrix, inflammatory response, and organ-to-organ crosstalk. We summa-
rize therapeutic strategies targeting known regulators of exercise-induced protection and the
challenges translating findings from bench to bedside. We conclude that technological advance-
ments that allow for in-depth profiling of the genome, transcriptome, proteome and metabolome,
combined with animal and human studies, provide new opportunities for comprehensively defining
the signaling and regulatory aspects of cell/organelle functions that underpin the protective
properties of exercise. This is likely to lead to the identification of novel biomarkers and therapeutic
targets for heart disease.

I. INTRODUCTION, CLINICAL ... 419 exercise in clinical trials in heart failure patients have been
II. EFFECTS OF EXERCISE ON THE ... 420 well described (72, 88, 172, 298, 327, 449). Low-, moder-
III. GENOME, TRANSCRIPTOME, ... 448 ate-, and vigorous-intensity exercise have all been shown to
IV. THERAPEUTIC STRATEGIES: ... 454 provide some degree of benefit (68, 123, 225, 403).
V. OBSTACLES AND CHALLENGES 460 Whether a dose-response effect exists based on exercise du-
VI. PERSPECTIVES AND CONCLUSIONS 461 ration and/or intensity is debatable but has been reported
by some studies (68, 123, 218, 225, 403). Of note, there are
I. INTRODUCTION, CLINICAL also reports of very intense/extreme exercise causing dam-
PERSPECTIVE, AND OVERVIEW age to the human heart. This has recently been reviewed and
will not be discussed here (109). For the purpose of this
The benefits of regular exercise or physical activity in hu- review, the term exercise has largely been used to reflect
mans on the heart and other organs in settings of health and regular aerobic or endurance exercise, unless otherwise
disease are well recognized (322). Exercise is known to stated.
reduce the risk of cardiovascular disease and cardiac events
in males and females of the young and aged. The survival Given many individuals do not exercise or are unable to
rate after a cardiovascular event is also greater in physically exercise, there has been intense investigation into delineat-
active individuals compared with more sedentary individu- ing the key mechanisms responsible for exercise-induced
als (39, 68, 205, 224, 291, 436), and the beneficial effects of protection. Exercise represents a very complex stimulus af-

0031-9333/18 Copyright © 2018 the American Physiological Society 419

 BERNARDO ET AL.
fecting numerous organs and cell types. Exercise has direct
beneficial effects on multiple cell types within the heart, but
also has effects on other systems (e.g., vascular system, skel-
etal muscle, brain, adipose tissue) which can have second-
ary effects on the heart (4, 151, 198, 206, 371). The cross-
talk between numerous organs and tissues in health and
disease has emerged as an important piece of the puzzle
when understanding disease processes, progression, preven-
tion, and treatment (188, 321). The aim of harnessing or
exploiting the beneficial effects of exercise represents an
active and exciting area of research. By comprehensively
understanding the factors underlying the protective proper-
ties of exercise, the hope is that we can develop improved
therapies including preventative and treatment strategies.
The goal of this review is to highlight known underlying
mechanisms responsible for exercise-induced cardiac pro-
tection, as well as to highlight new avenues for research.
Studies in genetic mouse models have been invaluable in
allowing investigators to use a reductionist approach to
identify key mediators of exercise-induced protection, and a
description of these studies represents a large portion of this
review. While different modes and intensity of exercise have
been tested in humans with respect to cardiovascular dis-
ease, the most commonly used exercise rodent models to
understand the beneficial effects of exercise at the cellular
and molecular level include chronic aerobic models such as
swim training (2–5 wk: a ramp protocol from 10 to 90 min
sessions twice a day, 5–7 days/week), treadmill running
(4 – 6 wk: a ramp protocol from 10 min/day to 60 min/day,
5–7 days/week; ⬍70% VO2 maximal oxygen uptake), and
voluntary free wheel running (4 – 8 wk) (29). Unless other-
wise stated, these or comparable protocols have been used
when referring to swim, treadmill, or voluntary running
throughout the text.
In this review we discuss in detail the effects of exercise on
cardiomyocytes as well as other cardiac cell types, organ-
elles, and systems that have received less or little attention
and require much further investigation. This includes the
impact of exercise on cardiac excitation and contraction,
mitochondrial adaptations, cellular stress responses to pro-
mote survival (heat shock response, ubiquitin-proteasome
system, autophagy-lysosomal system, endoplasmic reticu-
lum unfolded protein response, DNA damage response),
extracellular matrix, inflammatory response, and organ to
organ crosstalk. We summarize technological advance-
ments that allow for in-depth profiling of the genome, tran-
scriptome, proteome, and metabolome in response to exer-
cise. We also describe how these methodologies combined
with animal and human studies provide new opportunities
for comprehensively defining cellular and molecular mech-
anisms that underpin the protective properties of exercise.
Finally, this is followed by a description of therapeutic
strategies targeting known regulators of exercise-induced
protection in small animals, large animals, and clinical trials
420 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
and the challenges translating findings from bench to bed-
side.
II. EFFECTS OF EXERCISE ON THE
CARDIOVASCULAR SYSTEM
To meet the oxygen demands of muscle in response to ex-
ercise, a number of changes take place to allow the heart to
pump more blood each minute to increase cardiac output
three- to sixfold. During settings of acute exercise, the body
initially responds with activation of the sympathetic ner-
vous system and downregulation of the parasympathetic
nervous system. Release of catecholamines [epinephrine
(E), norepinephrine (NE)] increase heart rate and cardiac
contractility, while blood flow to the heart and exercising
skeletal muscle is increased via local vasodilator mecha-
nisms (FIGURE 1A). This together with vasoconstriction in
the periphery to maintain/increase blood pressure leads to
an increase in blood flow back to the heart (venous return).
Collectively, the increase in heart rate and stroke volume
increases cardiac output (159) (FIGURE 1A). The increased
blood flow to the heart during exercise stretches the walls of
the heart, leading to an increase in the force of contraction
(Frank-Starling mechanism) and the quantity of blood leav-
ing the heart. In response to chronic or long-term regular
exercise which is accompanied by increased sympathetic
activity, and release of hormones and growth factors, the
heart walls thicken and the size of the heart increases (FIG-
URE 1B). The process of cardiac enlargement normalizes
wall stress/tension [Laplace’s law: wall stress ⫽ (pressure ⫻
radius)/(2 ⫻ wall thickness)], allowing the heart to main-
tain normal heart function. This type of cardiac enlarge-
ment is referred to as physiological cardiac hypertrophy
and is very different at the functional, histological, and
molecular level to pathological cardiac hypertrophy,
which occurs in cardiac disease settings (35). Physiolog-
ical cardiac hypertrophy is characterized by increased
heart mass, normal/enhanced cardiac function, and no
evidence of cardiac fibrosis [excessive deposition of ex-
tracellular matrix (ECM) proteins] or cell death (FIGURE
1B). In contrast, pathological cardiac hypertrophy is typ-
ically characterized by depressed heart function, cardiac
fibrosis, and cell death; increased expression of cardiac
stress markers [e.g., atrial natriuretic peptide (ANP) and
B-type natriuretic peptide (BNP)]; and a fall in proteins
critical for cardiac contraction [e.g., ␣-myosin heavy
chain (␣MHC) and sarco/endoplasmic reticulum Ca2⫹-
ATPase (SERCA2a)]. Pathological cardiac hypertrophy
is also an independent risk factor for heart failure (35).
A. Exercise-Induced Cardiac Remodeling
Exercise-induced cardiac remodeling is a complex process
that involves exercise-induced stimuli (catecholamines, me-
chanical stretch, hormones, and growth factors) regulating
 EXERCISE-INDUCED CARDIAC PROTECTION

A ACUTE B CHRONIC
EXERCISE EXERCISE

Sympathetic activity
Hormones
Muscular &
respiratory pumps ↑ Sympathetic ↓ Parasympathetic
engaged activity activity Growth factors

AD

↑E Physiological cardiac hypertrophy

↑ NE &
↑ NE

↑ Venous return Sinoatrial node ↑ Heart mass

Normal/enhanced heart function
SAN
↑ EDV Protection against fibrosis, cell death &
heart failure

↑ Cardiac contractility
Frank Starling
mechanism

↑ Stroke volume ↑ Heart rate

↑ Cardiac output

FIGURE 1. Systemic and cardiac effects of acute and chronic exercise. A: an overview of the effects of acute
exercise on the cardiovascular, sympathetic nervous system, and adrenal medulla, which together increase
cardiac output. B: chronic or long-term exercise is associated with increased sympathetic activity as well as
release of hormones and growth factors that act as stimuli to regulate physiological cardiac hypertrophy.
Physiological heart growth protects the heart from fibrosis, cell death, and heart failure. E, epinephrine; EDV,
end-diastolic volume; NE, norepinephrine. This figure provides a general overview of acute and chronic changes
with aerobic exercise such as jogging, swimming, and cycling. However, it is noteworthy that exercise of
different types, duration, and intensity can have varying effects.

numerous processes within cardiac cells. The adult mam-
malian heart contains multiple cell types including cardiac
myocytes, fibroblasts, endothelial cells, leukocytes, and mu-
ral cells (vascular smooth muscle cells and pericytes). To
date, mechanisms within cardiac myocytes are best de-
scribed. It is generally accepted that cardiac myocytes rep-
resent 30 – 40% of the cell population in the adult rodent
and human heart, and this represents 70 – 85% of the
heart’s volume. The percentage and contribution of non-
myocytes has remained debatable, largely due to the use of
different analytical methods and inadequate tools/markers
(328, 465). However, based on a recent study using a com-
bination of genetic tools and cellular markers, the adult
mouse heart consists of ~30% cardiac myocytes, 45% en-
dothelial cells (majority representing vascular endothelial
cells), 11% fibroblasts, 8% mural cells, and 6% leukocytes
(328). In the subsequent section we discuss the effects of
exercise on cell types, organelles, and key processes within
the heart including 1) adaptations to cardiac myocytes in-
cluding hypertrophy and proliferation, 2) vascular adapta-
tions, 3) electrical activity and excitation-contraction (E-C)
coupling, 4) mitochondrial adaptations (energy metabolism
and redox status), 5) cellular stress responses (survival and
death), 6) maintenance of the ECM, and 7) communication
with other organs (FIGURE 2).
B. Adaptations to Cardiac Myocytes:
Hypertrophy and Proliferation
In the adult heart, cardiac enlargement occurs largely due
to a parallel increase in cardiac myocyte size because the

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 BERNARDO ET AL.

VASCULAR ADAPTATIONS

CARDIAC HYPERTROPHY
EXCITATION-CONTRACTION COUPLING ↑eNOS ↑NO MYOCYTE GROWTH & PROLIFERATION

Hypertrophy
Angiogenesis

Myocyte
Myocyte

EXERCISE Proliferation

Myocyte

MITOCHONDRIAL ADAPTATIONS

Differentiation &
↑ Sympathetic activity Myocytes
Proliferation
eCSC

↑ Hemodynamic load &

mechanical stretch
ANTI-FIBROTIC ACTIONS
Release of hormones &
CELLULAR STRESS RESPONSE growth factors
Extracellular matrix in disease settings
Proteasome-ubiquitin ↑ Collagen ↑ TIMPs ↓ MMPs
system

Misfolded protein COMMUNICATION

WITH OTHER ORGANS
ER stress Fibrosis
Myocytes
unfolded protein Liver
response

Adipose
tissue
Skeletal
muscle
FIGURE 2. Effects of exercise on cardiac and vascular cells, and cross talk with other organs. In response
to exercise, there are direct effects on different cell types, organelles, and biological processes within the heart
as well as other organs which may have secondary effects on the heart and the rest of the body. These include
myocyte hypertrophy and proliferation, vascular adaptations, excitation-contraction coupling, mitochondrial
adaptations, cellular stress responses, antifibrotic actions, and communication with other organs. The illus-
tration of the female jogging in this figure and subsequent figures has been used as a general symbol to
represent “exercise.” Specific details regarding the type of exercise, duration, and intensity are provided within
the text or TABLE 1.

heart has a very limited capacity for myocyte prolifera-
tion or renewal (331, 390, 391). In response to exercise,
hypertrophy of cardiac myocytes also appears to be the
predominant factor responsible for heart enlargement
(62, 269, 446). However, there are also studies to sup-
port the existence of cardiomyocyte proliferation in the
adult mammalian heart and enhancement in a setting of
exercise. Exercise training in mice (treadmill running or
swimming) was reported to induce cardiac myocyte pro-
liferation and renewal (up to ~7%), potentially from en-
dogenous cardiac stem/progenitor cells (eCSCs) or pre-
existing cardiac myocytes (25, 44, 373, 445, 452). How-
ever, further studies examining the significance of
exercise-induced cardiomyocyte proliferation are re-
quired. A recent study showed that inhibition of cell pro-
liferation in mice (via administration of an antineoplastic
agent 5-fluorouracil) before swim training did not pre-
vent exercise-induced heart growth, suggesting that car-
diac cell proliferation is not required for physiological
cardiac hypertrophy (19). However, cardiac cell prolifer-
ation does appear to be essential for exercise-induced
protection against ischemia-reperfusion injury because
the same agent (5-fluorouracil) abolished the cardiopro-
tective effect of exercise (19). The molecular pathways
associated with cardiac myocyte hypertrophy and prolif-
eration are discussed below.
Numerous growth factors are released in response to
exercise and have the capacity to induce cardiac enlarge-
ment (i.e., physiological cardiac hypertrophy). These in-

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 EXERCISE-INDUCED CARDIAC PROTECTION

clude insulin-like growth factor 1 (IGF1), hepatocyte 1. IGF1-PI3K-Akt signaling axis

growth factor (HGF), platelet-derived growth factor
(PDGF), vascular endothelial growth factor (VEGF), and
neuregulin-1 (NRG1) (83, 445, 459). Of these, IGF1 and
signaling downstream of the IGF1 receptor (IGF1R), i.e.,
phosphoinositide 3-kinase (PI3K; class 1A: p110␣ and
␤)-Akt signaling, is the best-characterized pathway for
mediating exercise-induced myocyte hypertrophy. How-
ever, many of the other aforementioned growth factors
are also able to activate PI3K-Akt signaling (FIGURE 3). It
has been suggested that exercise promotes cardiac cell
proliferation and renewal via 1) sympathetic activity and
growth factors (IGF1, NRG1, and HGF) inducing eCSC
proliferation (431, 452), and 2) bone morphogenetic
protein 10 (BMP-10) and transforming growth factor ␤1
(TGF-␤1) stimulating the differentiation of eCSCs into
cardiac lineages (431, 445) (FIGURE 3).
IGF1 is a growth factor released in response to exercise in
animal models and elite athletes (212, 460), and the cardiac
formation of IGF1 was elevated in male soccer players with
exercise-induced hypertrophy in comparison to healthy in-
dividuals (301). Based on studies utilizing gain- and loss-of-
function genetically modified mouse models, it is now well
recognized that the IGF1-IGF1R- insulin receptor substrate
(IRS)-PI3K (class 1A)-phosphoinositide-dependent protein
kinase-1 (PDK1)-Akt1 axis plays a key role in regulating
exercise-induced heart growth (FIGURE 3 AND TABLE 1).
This section is focused on mechanisms within cardiac myo-
cytes, but it is noteworthy that PI3K-Akt signaling and
downstream regulators also play a role in endothelial cells
in response to exercise, as described in section IIC. IGF1
activates the IGF1R upon binding. This subsequently re-
cruits the IRS adaptor proteins (IRS1/IRS2) which then ac-

EXERCISE DISEASE SETTINGS

e.g. hypertension
↑ Sympathetic
activity
Growth
Thyroid Growth Factors
hormone NRG1 Synd-4
Growth IGF1 hormone e.g. VEGF, PDGF, HGF
factors
β2-AR IGF1R

ErbB4 β-AR AT-R

eCSCs
IRS1/2 PI3K
p110α/β
P
Signaling contributing
AMPK
to pathological hypertrophy
PGC-1α PDK1 PAK1
P e.g. Calcineurin
JAK2 PKCβ
↑ Survival MAPKs
↑ Proliferation PHLPP1 P P

(IGF1, NRG1, HGF) P P AKT1 GSK3β

PP2A STAT3
Physiological
SIX1 signaling ↑ ROS
mTOR
BMP-10 Thyroid
hormone EYA2
Raptor
PRAS40
[mTORC1 eIF2Bε ↑ Fibrosis
↑ Apoptosis
TGF-β1
Myocyte
cytosol 4E-BP1 S6K1
Differentiation into
myocytes, capillaries HEART FAILURE
PHYSIOLOGICAL
HYPERTROPHY

P Nucleus
AKT1
SIX1
Expression of Cardiomyocyte
mTOR exercise/adaptive survival, PHYSIOLOGICAL
EYA2 PI3K? SRF C/EBPβ genes e.g. proliferation HYPERTROPHY
Gata4, αMHC and growth

Growth Thyroid Expression of

IGF1 CITED4 ? cardiac genes
hormone hormones
e.g. MHCs, Serca2a

FIGURE 3. A schematic of the major signaling pathways involved in exercise-induced cardiac hypertrophy.
The major signaling pathway implicated in exercise-induced cardiac hypertrophy is the IGF1-PI3K-Akt pathway.
Thyroid hormones, NRG1 signaling, growth factors, and Synd4 have also been shown to regulate the IGF1-
PI3K-Akt pathway. Physiological signaling has been shown to inhibit pathological cascades (shown in red).
Dashed lines indicate translocation to a different intracellular compartment, and dotted lines indicate mech-
anisms that are not yet well understood. Signaling is complex, and there is cross talk between various
components of the pathways (not all illustrated).

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 BERNARDO ET AL.

Table 1. Genes regulating exercise-induced cardiac remodeling

Reference
Gene and Model Exercise Model Observation Nos.

IGF1R: cardiac myocyte Swim exercise: ramp protocol followed Hypertrophic growth blunted in IGF1R 203
specific KO of IGF1R by 90 min sessions twice/day for 4 KO mice.
wk (total ~5 wk)
IGF1R: cardiac myocyte Swim exercise: ramp protocol followed Augmented cardiac hypertrophic 267
specific transgenic by 90 min sessions twice/day for 3 response in IGF1R transgenic.
overexpression of wk (total ~4 wk)
IGF1R
PI3K: cardiac myocyte Swim exercise: ramp protocol followed dnPI3K transgenic mice displayed a 269, 310
specific by 90 min sessions twice/day for blunted hypertrophic response to
dnPI3K(p110␣) 2–3 wk (total ~3–4 wk) exercise compared with Ntg.
transgenic Mitochondrial adaptations also
attenuated.
PI3K: muscle specific Swim exercise: ramp protocol followed Exercise-induced hypertrophy 247
KO of PI3K (p110␣ by 90 min sessions twice/day for 3 attenuated in KO.
and p110␤) wk (total ~4 wk)
IRS1: cardiac myocyte Swim exercise: ramp protocol followed No response to exercise-induced 347
specific deletion by 90 min sessions twice/day for 4 hypertrophy in KO.
knockout of IRS1 wk (total ~5 wk)
IRS2: cardiac myocyte Swim exercise: ramp protocol followed KO mice exhibit baseline cardiac 347
specific deletion by 90 min sessions twice/day for 4 hypertrophy and no response to
knockout of IRS2 wk (total ~5 wk) exercise-induced hypertrophy.
PDK1/PDPK1: cardiac Swim exercise: ramp protocol followed Exercise-induced hypertrophy 307
myocyte specific by 90 min sessions twice/day for 4 prevented in cPDPk1⫹/–. No effect
heterozygote wk (total ~5 wk) on mitochondrial adaptations
knockout of PDPK1 associated with exercise.
(cPDPk1⫹/–)
PAK1/(potential Treadmill endurance running for 6 wk Exercise-induced hypertrophy, cardiac 85
PDK2): global KO (55–60% maximal aerobic velocity, contractility, myofilament calcium
15% incline, 60 min/day, 5 sensitivity, and posttranslational
days/week) modification of sarcomeric proteins
were blunted in PAK1 KO mice.
Akt1: global KO Swim exercise: 90 min sessions Exercise-induced hypertrophy 91
twice/day for total ~3 wk attenuated in KO.
Akt1 KO and kdAkt Swim exercise: ramp protocol followed Exercise-induced hypertrophy blunted 310
by 90 min sessions twice/day for 2 but no effect on mitochondrial
wk (total ~3 wk) adaptations.
HSF1: HSF1-deficient Voluntary wheel running for 4 wk Equivalent hypertrophy in WT and 359
heterozygote HSF1⫹/–. Cardiac dysfunction in
(HSF1⫹/–) mice HSF1⫹/–.
Heterozygote C/EBP␤ Swim exercise: ramp protocol followed Under basal condition, heterozygote 44
(complete KO not by 90 min sessions twice/day for 2 mice display cardiac hypertrophy
viable) wk (total ~3 wk) associated with myocyte
hypertrophy and proliferation.
There is a minimal increase in
heart size in response to swim
training.
Protein phosphatase Swim exercise: ramp protocol followed Exercise-trained PHLPP1 KO mice 282
PHLPP1: KO by 90 min sessions twice/day for 2 showed an exaggerated
wk (total ~3 wk) physiological hypertrophic
response.
Activation of Akt by PHLPP1 KO mice had elevated
PHLPP1 deletion angiopoietin-2 and VEGF-A levels
and increased myocardial capillary
density compared with control
mice.
PRAS40 4 wk of voluntary wheel running Physiological hypertrophy was not 429
blocked by PRAS40 overexpression
but was inhibited by phospho-dead
mutant PRAS40TA.
Continued

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 EXERCISE-INDUCED CARDIAC PROTECTION

Table 1.—Continued
Reference
Gene and Model Exercise Model Observation Nos.

eNOS KO 8 wk of voluntary wheel running (~7 Exercise was unable to attenuate MI- 90
km/day) induced ventricular remodeling,
hypertrophy, fibrosis, and apoptosis
in eNOS KO mice.
Of note,eNOS KO mice Skeletal muscle may be the source of 59
were reported to eNOS.
exercise to a lesser
degree than WT in
other references but
not this reference
␤3-AR KO 4 wk of voluntary wheel running Exercise was less effective in 58
exercise protecting KO mice from IR injury.
Of note, ␤3-AR KO
exercise to a lesser
degree than WT
(~50% less)
␤1-AR KO Graded treadmill exercise (speed and The normal exercise-induced increase 351
angle inclination were progressively in heart rate was blunted in ␤1-AR
increased) KO, but this did not impact on
maximal exercise capacity.
RyR2-S2808A Swimming in untrained mice for 5 min Mutant mice had impaired exercise 378
mutation (knock-in capacity.
mouse-global)
Mouse lacks the major Note: Authors cannot exclude the
PKA phosphorylation possibility that extracardiac factors
site on RyR2 contributed to the impaired
exercise capacity.
NOS1-KO mice 8 wk aerobic interval training program Exercised NOS1-KO mice did not have 354
(treadmill) cardiac hypertrophy or increased
VO2max compared with sedentary
NOS1-KO mice.
nNOS-KO mice 8 wk aerobic interval training program Exercised nNOS-KO mice have 353
(treadmill) decreased ejection fraction and
increased ROS production.
nNOSOE No exercise protocol–goal to nNOSOE myocytes exhibited 353
(overexpression) mice determine if overexpression could enhanced contraction and
recapitulate the exercise training relaxation, and a higher VO2max.
state in sedentary lifestyle
Synd4 KO mice Swim exercise: ramp protocol followed KO mice exhibited a blunted cardiac 453
by 90 min sessions twice/day for 3 hypertrophic response compared
wk (total ~4 wk) with WT mice following 4 wk of
swim training.
Male global AMPK␣2 Swim training for 4 wk in total (50 Exercise training in control mice 248
KO min/day, 6 days/week following a attenuated isoproterenol (␤-AR
ramp protocol) agonist)-induced ROS and fibrosis
(isoproterenol administered in the
last 2 wk of swim training).
Protection was not observed in
AMPK␣2 KO mice. Note: AMPK ␣2
is abundant in skeletal muscle.
Comprehensive evidence
demonstrating KO mice exercised
to the same degree as control
mice was not included.
Continued

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 BERNARDO ET AL.

Table 1.—Continued
Reference
Gene and Model Exercise Model Observation Nos.

Cardiac-specific Swim training for 22 days in total (90
deletion of Gata4
(reduced Gata4 by
E17.5 and into
adulthood by crossing
floxed mice with Cre
from the ␤MHC
promoter)
Inducible, cardiac Basal phenotype
specific CITED4
transgenic mice
Gata4-deleted mice developed
min/twice a day, 7 days/week
following a ramp protocol)
15–20% increase in heart weight,
313
hypertrophy in response to swim
training, but the magnitude was
blunted compared with control
mice (36% increase in VW/BW in
control mice, 26% increase in
Gata4-deleted mice). Note: Gata4-
deleted mice display cardiac
dysfunction under basal conditions
by 12 wk of age and apoptosis. It
was not clear what age mice began
swimming, but it is stated that
mice were monitored continuously
to ensure equal exertion.
37
concentric hypertrophy without an
increase in fibrosis, no difference in
lung weight, no difference in
fractional shortening. This
phenotype is similar to what is seen
after endurance training in mice.

BW, body weight; KO, knockout; MI, myocardial infarction; VW, ventricular weight; WT, wild type. Unless stated otherwise, most swim studies
have used a ramp protocol typically starting at 10 min/twice a day and increasing 10 min/day ⱕ90 min sessions/twice a day.

tivates the PI3K-PDK1-Akt1 pathway. The p110␣ isoform
of PI3K (class 1A PI3K) was the first gene shown to play a
critical role for exercise-induced cardiac hypertrophy. Car-
diac-myocyte specific transgenic mice expressing a domi-
nant negative PI3K mutant (dnPI3K) displayed a markedly
reduced hypertrophic response to 4 wk of chronic swim
training compared with nontransgenic littermates (269). In
contrast, dnPI3K transgenic mice developed a robust hyper-
trophic response to the pathological stimulus of chronic
pressure overload (269). Subsequent to this discovery, the
critical role of PI3K has been confirmed by other studies,
and the role of genes upstream and downstream of PI3K
have been interrogated. Swim exercise training in mice for
3–5 wk induces a reproducible increase in heart size that
was blunted or prevented in mice with deletion or reduced
activity of IGF1R, IRS1, IRS2, class IA PI3K(p110␣ ⫹/⫺
p110␤), PDK1, and Akt1 (91, 203, 247, 269, 307, 310,
347). Regulators of Akt and the mammalian target of rapa-
mycin complex 1 (mTORC1), P21-activated kinase (PAK1;
252), and proline-rich Akt substrate of 40 kDa (PRAS40)
have also been identified as key regulators of exercise-in-
duced physiological heart growth (85, 429) (FIGURE 3, TA-
BLE 1).
Distal to Akt, signaling and crosstalk become more com-
plex. For instance, deletion of ribosomal S6 kinases (S6K1
and S6K2; downstream effectors considered important for
protein synthesis) had no effect on swim-induced cardiac
hypertrophy (268). It remains unclear whether compensa-
tory mechanisms were responsible for exercise-induced car-
diac enlargement in S6K1/2 knockout (KO) mice. In addi-
tion, while the IGF1 signaling cascade is typically presented
as a linear pathway for simplicity, it is recognized that sub-
stantial crosstalk between other pathways exist. For exam-
ple, exercise-induced cardiac hypertrophy was attenu-
ated in cardiac-specific KO models of IGF1R, IRS1, IRS2,
and cardiac-specific dnPI3K mice, but different down-
stream mechanisms have been implicated [e.g., decreased
pAkt, decreased pJAK2, increased dephosphorylation of
Akt, and altered regulation of adenosine monophos-
phate-activated protein kinase (AMPK)] (203, 269, 310,
347) (FIGURE 3).
2. Other regulators of Akt signaling
As described earlier, growth factors in addition to IGF1 are
elevated in response to exercise and have the potential to act
via other transmembrane receptors to activate Akt signaling
(FIGURE 3). The contribution of these alternate upstream
regulators in mediating different aspects of exercise-in-
duced remodeling are not well defined, and some redundan-
cies may exist. Syndecan-4 (a transmembrane proteogly-
can) was upregulated in rat hearts following 4 wk of high-
intensity aerobic swim training, and swim-induced cardiac
hypertrophy was largely prevented in Syndecan-4 KO mice
(453). However, this was a global KO mouse model, and
direct measures of exercise capacity between groups (con-
trol and KO) were not presented (453). Akt was implicated
in the blunted hypertrophic response because 1) the phos-
phorylation of Akt was lower in swim-trained Syndecan-4
KO mice, and 2) in cultured cardiac myocytes, Syndecan-4
overexpression induced myocyte enlargement, which was
blocked with an Akt inhibitor (453).

426 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org

 EXERCISE-INDUCED CARDIAC PROTECTION
A novel Akt phosphatase, PHLPP1 (PH domain leucine-
rich repeat protein phosphatase), has also been shown to
regulate exercise-induced hypertrophy. PHLPP1 dephos-
phorylates Akt, which in turn terminates Akt signaling. Un-
der basal conditions, PHLPP1 KO mice had increased Akt
activity but normal heart size and function. However, when
PHLPP1 KO mice underwent forced swim training for 20
days, cardiac hypertrophy was accentuated compared with
wild-type exercised mice (282).
3. Transcription factors regulated by exercise and
Akt signaling
CCAAT/enhancer binding protein ␤ (C/EBP␤; encoded by
CEBPB) and Cbp/p300-interacting transactivator with ED-
rich carboxy-terminal domain 4 (CITED4; encoded by
CITED4) have been identified as critical regulators of phys-
iological cardiac hypertrophy and cardiomyocyte prolifer-
ation (44) (FIGURE 3). C/EBP␤ expression was downregu-
lated in hearts of mice following an acute bout or 2 wk of
aerobic exercise training, but was unchanged in hearts of
mice with pathological cardiac hypertrophy induced by
aortic banding (44) and upregulated in the rat heart 3, 6,
and 12 h post-myocardial infarction (MI) (97). siRNA
knockdown of CEBPB in neonatal rat cardiomyocytes in-
duced hypertrophy and increased cell number, demonstrat-
ing that C/EBP␤ is a negative regulator of cardiomyocyte
hypertrophy and proliferation. Additionally, heterozygote
C/EBP␤ mice displayed many of the cardiac phenotypes
seen in exercised mice, i.e., increased heart and cardiomyo-
cyte size and improved cardiac function. Although mice
with genetically reduced C/EBP␤ levels displayed increased
exercise capacity under basal conditions, their hypertrophic
response following swim exercise training was not further
elevated. C/EBP␤ expression was shown to be regulated by
Akt1, as adenoviral overexpression of Akt1 in neonatal rat
cardiomyocytes reduced C/EBP␤ mRNA expression, and
adenoviral transfer of a dominant negative Akt1 mutant
increased C/EBP␤ mRNA levels (44). C/EBP␤ was shown to
interact with serum response factor (SRF), a transcription
factor that promotes transcription of ␣MHC and GATA
binding protein 4 (GATA4) (44). Boström et al. (44) postu-
lated that C/EBP␤ sequesters SRF; thus reductions in
C/EBP␤ expression would lead to the release of SRF, in turn
enhancing binding of SRF to serum response elements.
Downregulation of C/EBP␤ induces cardiomyocyte prolif-
eration via upregulation of CITED4 expression, a transcrip-
tion factor that is upregulated in the heart by exercise (44).
In the adult heart, inducible cardiac specific expression of
CITED4 resulted in a heart phenotype reminiscent of what
was seen after endurance training in mice, that is, increased
heart weight by 15–20%, preserved cardiac function, and
no evidence of fibrosis (37).
Another transcription factor regulated by exercise is the
eyes absent 2 (Eya2) gene. The potential role of Eya2 in the
heart was first identified when profiling genes associated
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
with the regression of pressure-overload induced hypertro-
phy in rats. Eya2 was confirmed as an antihypertrophic
gene in neonatal cardiomyocytes (454). Cardiac-specific
transgenic expression of Eya2 in mice (⬃20- to 30-fold
higher protein than control) was reported to induce a mild
hypertrophic response (~5– 8% increase in heart and myo-
cyte size) which was characteristic of physiological hyper-
trophy (normal heart function) (227). In a later study from
the same investigators, it was shown that Eya2 protein ex-
pression was increased in hearts of mice subjected to swim
exercise for 4 wk (226). However, in this subsequent report
which further characterized the same Eya2 transgenic mice,
a mild basal hypertrophic phenotype was not observed
(226). However, it was demonstrated that both swim train-
ing in wild-type mice and transgenic expression of Eya2
were associated with increased expression of a physiologi-
cal regulator in the heart, mammalian target of rapamycin
(mTOR). In addition, Eya2 was shown to act as a transcrip-
tional coactivator in complex with another transcription
factor, Six1, to directly upregulate mTOR. Finally, thyroid
hormone (T3; inducer of physiological cardiac growth) was
shown to increase Eya2 and Six1 protein levels in isolated
neonatal cardiac myocytes (226) (FIGURE 3).
4. Benefits of physiological heart growth and
components of IGF1-PI3K-Akt signaling in disease
settings
Studies in exercise-trained rodents and genetic models
where components of the IGF1-PI3K-Akt pathway have
been regulated show that physiological growth/signaling is
able to attenuate pathological heart enlargement/remodel-
ing and/or cardiac myocyte hypertrophy in cardiac disease
models (181, 266, 349, 415, 434, 437, 446). The molecular
mechanisms responsible will require further study but in-
clude the ability of the IGF1-PI3K-Akt axis to inhibit sig-
naling cascades downstream of GPCR, which have been
implicated in inducing pathological cardiac hypertrophy
(35, 439) (FIGURE 3). IGF1R and constitutively active (ca)
PI3K transgenic mice displayed a blunted hypertrophic re-
sponse to pressure overload, whereas dnPI3K transgenic
mice and Akt1 KO mice showed an exaggerated hypertro-
phic response; regulation of extracellular signal-regulated
kinase (ERK) activation was implicated (266, 267, 446).
Furthermore, heterozygote C/EBP␤ mice were resistant to
pathological remodeling and cardiac dysfunction induced
by aortic banding (44), and CITED4 transgenic mice were
protected in a model of ischemia-reperfusion injury via a
mechanism mediated by mTORC1 (37). Eya2 transgenic
mice were also protected against pressure overload-induced
pathological remodeling due to aortic constriction. How-
ever, the degree of protection differed in two studies. In the
initial report, Eya2 transgenic mice displayed a blunted hy-
pertrophic response to aortic constriction (227), but a later
report identified no significant difference in heart size (226).
However, in both studies, Eya2 transgenic mice showed
evidence of protection compared with control mice based
427
 BERNARDO ET AL.

on cardiac function, fibrosis, or molecular profile. In addi-
tion, there was evidence of preserved physiological signal-
ing in the disease model (226, 227). That is, in Eya2 trans-
genic hearts subjected to aortic-constriction, SERCA2a
gene expression was preserved, and there was increased or
preserved expression of regulators induced with physiolog-
ical hypertrophy (IGF1R, PI3K, Akt, gp130 and Hsp70)
and genes involved with cell proliferation and cell cycle
regulation (e.g., CREB1, CDK5, GATA4) (226, 227). The
cardioprotective effects of Eya2 are considered to be medi-
ated via the Eya2/Six1-mTOR signaling axis, and possibly
PI3K (226).
6. Essential processes accompanying exercise-
induced cardiac hypertrophy
For the maintenance of cardiac function with exercise-in-
duced physiological hypertrophy, cardiac growth must be
accompanied by numerous events including vascular adap-
tations, regulation of E-C coupling, mitochondrial adapta-
tions to regulate cellular energy and reactive oxygen species
(ROS), cellular stress responses, and regulation of the ECM.
These factors are described in section II, C–G.
C. Adaptations to Endothelial Cells

5. Relevance of the IGF1 pathway in humans:
exercise and disease settings
There is also evidence from human studies linking IGF1
with physiological cardiac hypertrophy and protection
against cardiovascular disease. Cardiac formation of IGF1
was elevated in trained competitive soccer players com-
pared with healthy controls, which was positively corre-
lated with left ventricular (LV) mass index, LV end diastolic
dimension index, and LV posterior wall thickness (301).
Furthermore, genotyping studies have identified a number
of polymorphisms in the genes encoding IGF1 and the
IGF1R that correlate with LV mass index (187). For in-
stance, a genotyping study of elite endurance athletes found
that polymorphisms in the genes encoding IGF1, IGF1R,
and myostatin (a negative regulator of IGF1 signaling) cor-
relate with LV mass (187). The effects of these polymor-
phisms on serum IGF1 levels and, more specifically, cardiac
formation of IGF1 are unclear or have not been assessed (9,
125, 187, 355, 421). Associations between lower serum
IGF1 levels with diabetes or cardiac-related disease have
been reported in some, but not all, studies (41, 421), possi-
bly due to environmental factors (125). In a large Dutch
cohort, absence of the wild-type IGF1 allele was associated
with lower serum IGF1 levels and an increased risk of type
2 diabetes, MI, and LV pathological hypertrophy (41, 421).
A polymorphism in IRS1 that reduces PI3K activity in vitro
was associated with increased MI severity scores in patients
with acute MI (242).
Endothelial cells line the heart chambers (endocardium)
and the small intramyocardial coronary arteries/capillaries.
The endothelium acts as a structural barrier but also re-
leases a number of substances that can regulate cardiac
structure and function, e.g., growth factors, vasocon-
strictors, vasodilators (52, 182). The vascular endothe-
lium of the coronary circuit controls coronary blood sup-
ply to the heart via interactions with smooth muscle cells
(FIGURE 4A). In contrast, endothelial cells in the myocar-
dial capillaries and in the endocardial endothelium are in
close proximity to cardiac myocytes, allowing for direct
communication between cardiac myocytes and endothe-
lial cells (FIGURE 4B) (52).
1. Vascular adaptations
Vascular adaptations can broadly be classified as functional
(changes in vasomotor control) and structural [angiogene-
sis (proliferation of blood vessels by sprouting from existing
vessels) and vascular remodeling]. For a comprehensive and
detailed review on this topic, the reader is referred to Ref-
erence 222. The subsequent text summarizes some of the
key changes observed with exercise, i.e., vasodilation of the
coronary vasculature and angiogenesis. The oxygen con-
sumption requirements of the heart increase with exercise
due to the faster heart rate, wall stress, and contractility.
The oxygen supply to the heart is predominantly enhanced
by an increase in coronary blood flow via vasodilation of
the coronary arterioles (159). In response to exercise, re-
lease of catecholamines as well as activation of the renin-

FIGURE 4. Role of exercise-induced NO in the endothelium (vascular and cardiac), vascular smooth muscle cells, and cardiac myocytes. A:
vascular endothelium and vascular smooth muscle cells. NO produced from eNOS in the coronary vascular endothelium diffuses into vascular
smooth muscle cells where it causes relaxation and results in vasodilation for increased blood flow. B: cardiac endothelium and cardiac
myocytes. eNOS and nNOS have distinct subcellular locations. eNOS is located in the endothelium and caveolae within cardiac myocytes, and
nNOS is preferentially localized in the SR. Exercise-induced shear stress, catecholamine release (acting on ␤3-AR), and release of growth factors
(e.g., VEGF) from cardiac myocytes (acting via the VEGFR-PI3K-Akt pathway in endothelial cells) contribute to an increase in NO in cardiac
endothelial cells. NO produced in cardiac endothelial cells can promote angiogenesis. The role of eNOS in cardiac myocytes appears to be derived
mainly from the coronary microvascular endothelium. Once NO has diffused into cardiac myocytes, it can inhibit ␤1-AR contractility [i.e.,
␤1-AR-cAMP-PKA induced phosphorylation of the L-type Ca2⫹ channel (LTCC), RyR2 and PLB], reduce mitochondrial respiration and O2
consumption, and induce myocyte relaxation (via cGMP). eNOS in caveolae plays a role in the positive inotropic response to sustained stretch
by increasing the RyR2 open probability. nNOS-derived NO may inhibit Ca2⫹ influx through the L-type Ca2⫹ channels and stimulate Ca2⫹ reuptake
via phosphorylation of PLB.

428 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org

 EXERCISE-INDUCED CARDIAC PROTECTION

A VASCULAR ENDOTHELIUM

EXERCISE &
SHEAR STRESS

Coronary vascular
endothelial cells eNOS NO

Diffusible NO

GTP cGMP
Vascular smooth
muscle cells
RELAXATION

B CARDIAC ENDOTHELIUM

EXERCISE &
SHEAR STRESS

eNOS Akt
Cardiac eNOS NO
endothelial cells
ANGIOGENESIS PI3K
NO

β3 VEGFR
Extracellular matrixFibrosis ROS NO EXERCISE
Myocyte Sympathetic VEGF
EXERCISE Diffusible activity
Sympathetic hypertrophy
activity NE

NE Myocyte
size
Myocyte β1 β3 Caveolae

cAMP NO eNOS
Mitochondrial
T-tubule
respiration
PKA ROS
LTCC cGMP
NO

NO P
nNOS
Stretch PLB
eNOS
SERCA2a
Caveolae RyR2

Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org 429

 BERNARDO ET AL.
angiotensin-aldosterone system and endothelin system all
act on receptors on the vasculature to cause vasoconstric-
tion to contribute to the redistribution of blood flow to-
wards the heart and exercising muscles. The coronary vas-
culature of the heart escapes these vasoconstrictor actions
via the production of factors such as nitric oxide (NO)
(159). Exercise is associated with an increase in vascular
shear stress due to the increase in heart rate which increases
blood flow, and this is associated with the release of factors
from the endothelium including NO (18). The sympathetic
nervous system is also activated with exercise, and this also
contributes to NO production via catecholamines acting on
␤3-adrenoceptors (␤3-ARs) (FIGURE 4).
NO is generated by NO synthases (NOSs). There are three
NOS isoforms: endothelial NOS (eNOS, NOS3), neuronal
NOS (nNOS, NOS1), and inducible NOS (iNOS, NOS2).
Under physiological settings and in response to exercise,
eNOS and nNOS appear to be the predominant isoforms
responsible for NO generation. iNOS is elevated in the
heart in settings of cardiac pathology (251, 372). The best
recognized role of NO under basal conditions and in re-
sponse to exercise is the regulation of vascular homeostasis
via eNOS. However, more recently, nNOS has also been
shown to play an important role in exercise-induced cardiac
protection. Small amounts of NO are produced in the heart
by the constitutive expression of eNOS and nNOS. eNOS is
present in coronary and endocardial endothelial cells, as
well as cardiac myocytes (FIGURE 4). nNOS is present in
cardiac autonomic nerves and ganglia, and preferentially
localized in the sarcoplasmic/endoplasmic reticulum (SR) of
cardiac myocytes (FIGURE 4B) (372). The subsequent sec-
tion describes the role of eNOS related mainly to the vas-
culature. The role of eNOS and nNOS related to calcium
handling in cardiac myocytes and redox balance is dis-
cussed in section IID1F.
Molecular mediators and mechanisms implicated or associ-
ated with increased eNOS expression and NO production
in endothelial cells include ␤3-ARs, PI3K-Akt signaling, and
microRNAs (miRNAs; e.g., miRNA-21), described in detail
in previous reviews (18, 159, 371). There is substantial
communication from endothelial cells to vascular smooth
muscle cells and cardiac myocytes, including the diffusion
of NO from endothelial cells to both cell types (463) (FIG-
URE 4). The production of endothelial NO causes relax-
ation of vascular smooth muscle cells (via cGMP signaling)
(FIGURE 4A). NO-induced vasodilatation allows blood flow
to be matched to metabolic demands during exercise. Fur-
thermore, stored NO metabolites in the circulation and
heart (nitrite and nitrosothiols) can be reduced to NO dur-
ing cardiac stress to protect the heart from ROS, patholog-
ical hypertrophy, and fibrosis (58, 59). Increased NO me-
tabolites have been identified in exercise-trained rodents
and humans (e.g., healthy young male endurance athletes,
430 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
i.e., ⬎3 sessions per week of vigorous aerobic-endurance
exercise for ⱖ 2 yr) (58, 59).
Voluntary running wheel exercise in mice for 4 wk was
associated with increased circulating levels of cat-
echolamines and increased protein expression of cardiac
␤3-ARs (expression in endothelial cells vs. cardiac myocytes
was not specifically assessed) (58). Followup studies in
␤3-AR KO mice showed that ␤3-ARs play a critical role in
regulating eNOS/NO levels in response to exercise, and for
mediating the protective effects of exercise. In a cardiac
stress model of ischemia-reperfusion injury, 4 wk of volun-
tary free wheel running provided protection. The mecha-
nism implicated was exercise-induced catecholamines caus-
ing eNOS-NO generation via ␤3-AR stimulation (58). Pro-
tection may also be mediated via mechanisms involving
␤3-AR NO production in cardiac myocytes (described in
section IID1A).
2. Angiogenesis
In a setting of cardiac myocyte hypertrophy, angiogenesis is
a key response for maintaining perfusion and an adequate
nutrient supply (50, 442). Evidence from human and ani-
mals studies suggests that angiogenesis/capillary density in-
creases at a similar rate as exercise-induced cardiac enlarge-
ment (104, 158). This is in contrast to cardiac-disease-in-
duced pathological hypertrophy where angiogenesis is
inadequate (35). Mechanisms implicated for exercise-in-
duced angiogenesis and endothelial repair include increased
VEGF, PI3K-Akt signaling, stem cell mobilization, and
miRNAs (e.g., miRNA-126) (371). In addition to commu-
nication from endothelial cells to cardiac myocytes, there is
also communication from cardiac myocytes to endothelial
cells. For example, in response to exercise, VEGF is secreted
from cardiac myocytes that signals to endothelial cells to
promote angiogenesis via PI3K-Akt signaling (21, 445,
463) (FIGURE 4B). Genetically modified mice with reduced
VEGF in heart and skeletal muscle had reduced muscle
capillary density, and this was associated with cardiac dys-
function and reduced exercise capacity on a treadmill (en-
durance and exhaustion tests) (314). However, because
VEGF was also reduced in skeletal muscle and this was
associated with exercise intolerance, interpretation is more
complicated than a cardiac-specific mouse model. Chronic
cardiac myocyte selective activation of PI3K via gene deliv-
ery was associated with enhanced capillary density in nor-
mal adult mice (8 wk associated with physiological hyper-
trophy) and mice with pathological hypertrophy due to aor-
tic-banding (10 wk after gene delivery) (434). Furthermore,
mice with expression of caPI3K specifically in cardiac myo-
cytes display physiological hypertrophy with normal heart
function, suggesting that angiogenesis was adequate in
these mice (302, 382). In contrast, while short-term trans-
genic expression of Akt (2 wk) induced physiological hyper-
trophy associated with normal function, longer term ex-
 EXERCISE-INDUCED CARDIAC PROTECTION
pression (6 wk) was associated with reduced capillary den-
sity and cardiac dysfunction (383).
D. Cardiac Excitation and Contraction
The heart is unique, in that it can contract independently of
stimulation from the nervous system. However, in a setting
such as exercise, the autonomic nervous system plays a key
role in allowing the heart to respond to meet the increased
demands of the body (see sect. IID1). The heartbeat origi-
nates from the sinoatrial node (SA) within the right atrium
of the heart which acts as a pacemaker, producing regular
electrical impulses. The SA node contains autorhythmic
cells which spontaneously “fire” (depolarize). The electrical
impulse (action potential, AP) is propagated through the
atria to the atrioventricular node (AV) and then passes via
the conducting Purkinje fibers to spread through the ventri-
cle. Contractile cardiac myocytes are excited by adjoining
cardiac pacemaker cells leading to a coordinated contrac-
tion of the atria and ventricle. The electrocardiogram
(ECG) provides a measure of the electrical activity of the
heart which represents an integrated readout of APs in dif-
ferent regions of the heart (FIGURE 5A). On the ECG, the
P-wave represents atrial depolarization followed by atrial
contraction, the QRS complex reflects ventricular depolar-
ization followed by ventricular contraction, and the T-wave
represents ventricular repolarization followed by ventricu-
lar relaxation. At the cellular level, the AP represents a
sequence of depolarizing inward currents (Na⫹ and Ca2⫹)
and repolarizing outward currents (K⫹) moving across the
membrane via channels/pumps of cardiac myocytes (82,
137, 297, 299, 336). In humans, the AP of cardiac myocytes
is composed of five phases (phase 0, depolarization; phase
1, brief early repolarization; phase 2, plateau phase of main-
tained depolarization; phase 3, repolarization; phase 4,
resting) (82) (FIGURE 5A). Ion channels in humans and mice
are generally highly conserved. However, there are differ-
ences in the shape/phases of the AP and surface ECG from
humans and mice due to the presence of different channels,
and some differences in the contribution and/or timing of
the opening/closing of channels (300, 360) (FIGURE 5, A
AND B). This is not surprising, considering the heart rate of
mice is ~10 times higher than humans, the mouse requiring
shorter APs. The subsequent text summarizes the role of
different currents contributing to the different phases of the
human AP and how these can change with exercise (see sect.
IID1). However, since many of the mechanistic studies have
been obtained from genetic mouse models, the key differ-
ence between the contribution of currents in human and
mouse myocytes have also been highlighted. Despite differ-
ences in the AP and ECG of mice and humans, mouse mod-
els have led to a better understanding of electrical remodel-
ing in the heart and the cause of arrhythmias in settings of
cardiac pathology (180).
Cardiac APs are initiated by a voltage-gated inward current
that causes depolarization of the cell membrane. In the ma-
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
jority of cardiac myocytes (atrial and ventricular), an in-
ward sodium current (INa) leads to the rapid depolarization
phase (phase 0), opening of fast Na⫹ channels (largely
NaV1.5) (112, 297) (FIGURE 5A). This is followed by a brief
period of repolarization (phase 1) due to voltage-gated tran-
sient outward currents (Ito; atria and ventricle of human
and mouse) and ultrarapid K⫹ currents (IKur; atria of hu-
man) (49, 178). In mice, Ito plays a more prominent role for
repolarization than in humans, reflected by the different
shape on the AP (229, 300) (FIGURE 5, A AND B). The hu-
man AP has a long plateau phase (phase 2) followed by a
rapid repolarization. In contrast, in mice there is an earlier
rapid repolarization via Ito, leading to a dramatic drop in
the amplitude of the AP by ~50 – 60% (FIGURE 5B). This is
followed by slowing of the mouse AP, represented by a
plateau phase shoulder in which another transient outward
current (IKslow) plays a role for repolarization (229). During
the plateau phase (phase 2 on human AP), there is a small
but constant inward L-type calcium current (ICaL; opening
of L-type Ca2⫹ channels). This plays an important role for
E-C coupling. E-C coupling refers to the excitation stimuli
(electrical AP) being linked/coupled to cardiac muscle con-
traction (FIGURE 5C). Calcium is the key mediator that cou-
ples electrical excitation to contraction by cycling in and out
of the cardiac myocyte during each AP (336). The initial
entry of Ca2⫹ into cardiac myocytes through L-type Ca2⫹
channels which occurs during phase 2 of the action poten-
tial (plateau phase) is insufficient to trigger contraction of
myofibrils. However, the ICaL increases the probability of
the ryanodine receptors (RyR) opening (type 2 in the heart,
RyR2) and leads to the release of Ca2⫹ from the SR into the
cytoplasm (a process known as calcium-induced calcium
release). The elevation in free cytoplasmic Ca2⫹ levels re-
sults in Ca2⫹ binding to troponin C in the myofilaments,
leading to cardiac contraction and mechanical systole (198,
336). In diastole, cardiac relaxation occurs in response to
removal of intracellular free and troponin C-bound Ca2⫹
by SERCA2a (removes the majority of Ca2⫹) together with
the Na⫹Ca2⫹ exchanger (NCX), the mitochondrial calcium
uniporter (MCU), and the sarcolemmal Ca2⫹-ATPase (FIG-
2⫹
URE 5C). As SERCA2a controls the uptake of Ca into the
SR, it plays important roles for cardiac relaxation, Ca2⫹
loading of the SR, and consequently the amount of Ca2⫹
available for release during cardiac myocyte contraction
(196). SERCA2a activity is regulated by phospholamban
(PLB/PLN). When PLB is unphosphorylated it binds to
SERCA2a and inhibits its activity. However, when PLB is
phosphorylated, it is removed from SERCA2a and no longer
inhibits its activity, and Ca2⫹ uptake into the SR increases
(198). PLB is largely phosphorylated by cAMP-dependent
protein kinase A (PKA) and Ca2⫹/calmodulin-dependent ki-
nase II (CaMKII) (196) (FIGURE 5C).
The repolarization of the human AP after phase 2 occurs in
response to delayed outwardly rectifying K⫹ currents (slow,
IKs and rapid, IKr; phase 3) (82). The difference in shape of
431
 BERNARDO ET AL.

PHASE 1
A HUMAN B MOUSE
Ito PHASE 2 R
SAN
IKs

PHASE 0
Atrium ECG
SAN AVN
ICaL IKr PHASE 3 P Q ST

AVN Purkinje Ito

INa IK1
ICaL
IKslow
Ventricle IK1 Ca2+ Na+ IK1
R
PHASE 4 INa
PHASE 4
ECG NCX 3Na+-2K+
PQS T
ATPase
+ +
Na K
C
EXERCISE
ACTION
POTENTIAL
↓ Parasympathetic ↑ Sympathetic
Ito IKs IKr IKur IKslow IK1 IKACh 3Na+-2K+
↓ Ach ↑ NE
ATPase
INa K+ K+ K+ K+ K+
Na+
a Kv4.2 KvLQT1 Kir3.1 M2 β1 AR
Kv4.3 Kv1.5 Kir2.1
Nav1.5 ERG Kir3.4

ATPase K+
Na+
Gαi Gαs
Sarcoplasmic ICaL
reticulum cAMP Ca2+
2+ PKA P Cav1.2
L-type Ca
channel b RyR2 c P
PLB CaMKII h ∆ATP K+
Ca2+
ICaL ATP
IKATP
PLB MCU Kir6.2
Cav1.2 Ca2+ Ca2+ 2+
SERCA2a Ca mPTP
Ca2+ Ca2+
f Ca2+
Ca2+ ATPase
Ca2+
DIASTOLE g
d Ca2+ Mitochondria Ca2+
Ca2+
SYSTOLE NCX

T-tubule Na+ T-tubule

e Myofilaments

FIGURE 5. The action potential (AP) and effects of exercise on E-C coupling. The ventricular AP from human
(A) and mouse (B). The AP represents an interplay of inward and outward currents. INa, sodium current; ICaL,
L-type Ca2⫹ current; Ito, transient outward K⫹ current; IKr, rapid component of the delay rectifier K⫹ current;
IKs, slow component of the delayed rectifier K⫹ current; IK1, inward rectifier K⫹ current. C: currents which
contribute to the AP in A are presented on the cell membrane together with key channel proteins. The AP
depolarizes the cell membrane (a) leading to activation of L-type Ca2⫹ channels in the t-tubule and Ca2⫹ entry
(b). Ca2⫹ then binds to ryanodine receptors (RyR2) on the sarcoplasmic reticulum (SR; c). This is followed by
large amounts of Ca2⫹ from the SR (referred to as Ca2⫹-induced Ca2⫹ release; d) which leads to myofilament
and cardiac contraction (e). For the heart to relax, cytoplasmic Ca2⫹ levels must be returned to diastolic levels,
allowing Ca2⫹ to dissociate from myofilaments. This occurs due to inactivation of extracellular Ca2⫹ entering
through the L-type Ca2⫹ channels, and Ca2⫹ being removed from the cytoplasm via SERCA2a (f), the
Na⫹/Ca2⫹ exchanger (NCX: forward mode), the plasma membrane Ca2⫹-ATPase (g), and the mitochondrial
calcium uniporter (MCU; h). In response to exercise there is 1) increased sympathetic activity, release of
catecholamines, and increased activation of the ␤1-AR-cAMP-PKA pathway which increases cardiac contrac-
tility via phosphorylation of the L-type Ca2⫹ channel, RyR2, and PLB; 2) reduced parasympathetic activity acting
via the M2 receptor; and 3) regulation of the KATP channel.

the mouse AP (i.e., plateau phase shoulder) is because IKs tential. This occurs in response to the extra Na⫹ and Ca2⫹
and IKr are not prominent repolarizing K⫹ currents in the (which entered the cell during the AP) being removed from
adult mouse heart (229, 300, 360) (FIGURE 5, A AND B). the cell and K⫹ entering the cell via the sodium/potassium
Despite the name, non-voltage-gated “inwardly” rectifying pump (Na⫹-K⫹-ATPase pump) and NCX (82, 297, 299)
K⫹ (Kir) currents also contribute to repolarization in hu- (FIGURE 5, A AND B). There are other Kir channels (i.e., in
man and mouse via outward K⫹ currents. IK1 contributes addition to IK1) that are important for normal heart func-
mainly during phase 3 and 4 (299). tion but are not considered to play a major role in AP
repolarization under normal physiological settings. How-
Return to the resting state (phase 4) requires restoration of ever, these currents are known to play an important role in
ion concentrations back to balanced states pre-action po- conditions such as exercise and include 1) acetylcholine-

432 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org

 EXERCISE-INDUCED CARDIAC PROTECTION
activated K⫹ current [IKACh greatest abundance in atria and
pacemaker cells but also considered to play a role in the
ventricle (138, 275)] and 2) ATP-sensitive K⫹ current
(IKATP). In contrast to the voltage-gated ion channels that
are regulated by changes in the electrical membrane poten-
tial (e.g., fast Na⫹ channels, L-type Ca2⫹ channel), IKACh
and IKATP channels are ligand-gated channels (138, 299).
1. Exercise-induced changes of the AP and E-C
coupling
Exercise has been shown to regulate the activity and/or
density of numerous channels, pumps, and processes asso-
ciated with the cardiac AP and E-C coupling (summarized
in TABLE 2). For the heart to meet the energetic demands of
exercise, there is an increase in heart rate and cardiac con-
tractility. This occurs in response to the autonomic nervous
system and hormones, which increase heart rate by acting at
the SA node, and by enhancing cardiac myocyte contractil-
ity by altering ion currents, pumps, and regulators/compo-
nents of E-C coupling (137). Under resting conditions, the
parasympathetic nervous system predominates and releases
acetylcholine which controls the human heart rate at
~60 –70 beats/min. During exercise the sympathetic ner-
vous system is activated and NE is released (mainly from the
postganglionic sympathetic neurons that innervate the
heart but also the adrenal medulla). NE activates ␤1-ARs
which are expressed throughout the heart (atrial and ven-
tricular myocytes, SA node, AV node). ␤-Adrenergic signal-
ing plays an important role in coupling heart function with
changing physiological demands. Short-term or acute acti-
vation of ␤-adrenergic signaling in the heart (as occurs with
exercise) increases heart rate via effects on the SA node, and
enhances systolic and diastolic function (contractility and
relaxation) by acutely increasing Ca2⫹. In contrast, long-
term chronic activation of ␤-adrenergic signaling as occurs
in disease settings results in Ca2⫹ overload of the SR, and
this leads to myocyte death (apoptosis and necrosis), car-
diac dysfunction, and heart failure (441).
The mechanisms responsi-
A) ␤-ADRENERGIC-RELATED MECHANISMS.
ble for the exercise-induced shortening of the AP and in-
creased heart rate are complex and not entirely understood;
some mechanisms may also differ between species (110).
However, there is evidence to suggest that ␤-adrenergic
stimulation increases heart rate via cAMP binding to ion
channels responsible for the funny current [If; hyperpolar-
ization-activated cyclic nucleotide-gated (HCN) channels
that conduct an inward pacemaker current] (137, 141,
451).
In both humans and rodents, cardiac contractility is in-
creased by ␤-ARs coupling to the stimulatory G protein
(Gs)-cAMP-PKA pathway, and exercise stimulates ␤-AR
signaling (185, 192, 283, 284) (FIGURE 5C). PKA phosphor-
ylates many proteins to mediate an increased rate of E-C
coupling including L-type Ca2⫹ channels, PLB (relieving
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
inhibition of SERCA2a), RyR2, troponin I, and myosin
binding proteins (36, 137). The phosphorylation of L-type
Ca2⫹ channels leads to an increase in Ca2⫹ entry into the
heart which increases Ca2⫹ release by the SR through
RyR2. Increased Ca2⫹, together with enhanced SR Ca2⫹
cycling, results in increased contraction.
There is also evidence that CaMKII is activated in response
to ␤-AR stimulation. Increased intracellular Ca2⫹ in re-
sponse of PKA-induced phosphorylation of L-type Ca2⫹
channels activates CaMKII (FIGURE 5C). CaMKII can also
phosphorylate the L-type Ca2⫹ channels, RyR2, and PLB
and thus, together with PKA, increase entry of Ca2⫹ into the
SR (78, 141, 441, 451). Treadmill aerobic interval training
in mice for 6 wk was associated with increased cardiac
myocyte contractility, larger calcium amplitudes, faster re-
laxation, phosphorylation of PLB, and increased activation
of CaMKII␦ (predominant cardiac isoform). Many of these
effects were inhibited by a CaMKII inhibitor [autocamtide-
2-related inhibitory peptide (AIP), although this inhibitor
may have some off target actions] (196, 451). In contrast,
excessive CaMKII is recognized to contribute to cardiac
pathology, heart failure, and arrhythmia (78, 285).
B) SERCA2A. Exercise such as chronic aerobic running has
been shown to increase cardiac myocyte contractility by
increasing SERCA2a Ca2⫹ uptake/activity or protein in
healthy animals as well as rodent models of cardiac disease
(63, 149, 177, 196, 424, 446). Ca2⫹ uptake by SERCA2a
can be enhanced by the direct regulation of SERCA2a tran-
scription and activity, or via the modification of regulatory
processes/factors, e.g., PLB phosphorylation or other pro-
tein posttranslational modifications (O-GlyNAcylation,
SUMOylation) (149). Furthermore, a number of exercise-
induced factors/triggers/signaling pathways including the
␤-adrenergic pathway, thyroid hormone levels (T3/T4), mi-
tochondrial biogenesis, miRNAs, and PI3K-Akt signaling
have been reported to regulate SERCA2a transcription
and/or protein (149).
C) MITOCHONDRIA.Mitochondria in cardiac myocytes play a
role in maintaining a physiological Ca2⫹ concentration in
the cytoplasm by acting as a buffer for elevated Ca2⫹ that
can have an adverse effect on myocyte function. Cellular
Ca2⫹ is largely stored in the SR, and mitochondria located
near Ca2⫹-release sites on the SR capture released Ca2⫹.
The MCU is considered an important regulator of how
much Ca2⫹ enters the mitochondria (FIGURE 5C). At resting
Ca2⫹ levels the activity of the MCU in the heart is low.
However, with increased Ca2⫹ cycling due to inotropic
drive or augmented work load, MCU activity is enhanced to
allow faster Ca2⫹ loading of the mitochondria. In an induc-
ible cardiac-specific KO mouse model of MCU, basal mito-
chondrial Ca2⫹ was not affected and mice showed no ob-
vious phenotype. However, the KO model displayed intol-
erance to acute treadmill exercise, suggesting that the MCU
433

Table 2. Exercise-mediated regulation of channels/pumps/processes associated with the cardiac AP and E-C coupling
Current/Pump/Process
INa: sodium current
Ito (Ito,f and Ito,s)
Ito,f: transient outward current,
fast
Ito,s: transient outward current,
slow
IKur: delayed rectifier, ultra
rapid (human)
IKslow (IKslow1, IKslow2)
IKslow1: rapidly activating, slowly
inactivating delayed rectifier
current (mouse)
IKslow2: delayed rectifier with
slower inactivation kinetics
than IKslow1 (mouse)
ICaL: calcium current, L-type
IKr: delayed rectifier, rapid
(smaller role in mouse)
IKs: delayed rectifier, slow (role
in mice unclear but gene
present)
IK1: inward rectifier
434 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
BERNARDO ET AL.
Protein Gene Key Features Impact of Exercise/caPI3K
Nav1.5 SCN5A Phase 0 of human AP Swim training in mice 1Scn5a (455)†
Voltage activated caPI3K: 1Scn5a (455)†
Ventricle and atria: human and
mouse (299)
Phase 1 of human AP Swim training in mice 1current amplitude,
1Kv4.2, 1KCND2, 1KCND3 (455)
Kv4.2 KCND2 Voltage activated caPI3K: 1current amplitude, 1Kv4.2,
1KCND2, 1KCND3 (455)
Kv4.3 KCND3 Ventricle and atria: human and Transgenic model of DCM: 2current
mouse (299) amplitude and density, 2KCND2,
2KCND3. Most defects attenuated by
swim training or caPI3K (456)
Kv1.4 KCNA4 Voltage activated TAC model: caPI3K prevented a 2Ito,f
current density and 1 current amplitude
(456)‡
Ventricle and atria: human and Ito,s not specifically assessed
mouse (299)
Kv1.5 KCNA5 Phase 1 of human AP
Voltage activated
Atria: human (299)
Same protein and gene as IKur Swim training in mice 1current amplitude
in humans. of IKslow, 1Kv2.1, 1Kcnb1 (455)
Kv1.5 KCNA5 Ventricle and atria: mouse caPI3K: 1current amplitude and density
(299) of IKslow, 1Kv2.1, 1Kcnb1 (455)
Kv2.1 KCNB1 Ventricle and atria: mouse Transgenic model of DCM: 2current
(299) amplitude and density of IKslow, 2Kcna5
2Kcnb1. Defects attenuated by swim
training or caPI3K (456)
TAC model: caPI3K prevented a 2IKslow
current density and 1current amplitude
(456)‡
Cav1.2 CACNA1C Phase 2 of human AP Swim training in mice 1Cacna1c (455)†
Voltage activated caPI3K: 1current amplitude and density
of ICa, 1Cacna1c (455)
Ventricle and atria: human and
mouse (299)
HERG/ KCNH2 Phase 3 of human AP Swim training in mice 1mERG (455)†
mERG
Voltage activated
Ventricle and atria: human and
mouse (299)
KvLQT1 KCNQ1 Phase 3 of human AP Swim training in mice 1Kcnq1 (455)†
Voltage activated caPI3K: 1Kcnq1 (455)†
Ventricle and atria: human.
Not reported in mice but
gene present (299, 455)
Kir2.1 KCNJ2 Phase 3 and 4 of human AP Swim training in mice 1current amplitude
and density, 1Kir2.2, 1Kcnj2,
1Kcnj12 (455)
Kir2.2 KCNJ12 Voltage activated caPI3K: 1current amplitude and density,
1Kir2.2, 1Kcnj2, 1Kcnj12 (455)
Continued
 EXERCISE-INDUCED CARDIAC PROTECTION

Table 2.—Continued
Current/Pump/Process Protein Gene Key Features Impact of Exercise/caPI3K

Ventricle and atria: human and Transgenic model of DCM: no change in

Iss: delayed rectifier
Currents below do not appear
to contribute directly to the
normal AP based on Ref.
299
IKAch: acetylcholine-regulated
K⫹ current (contribution in
mouse unclear)
IKATP: ADP activated K⫹
channel
NCX
SERCA2a and PLB
mouse (299) current amplitude but 2density,
2Kcnj2, 2Kcnj12. Exercise and caPI3K
1current amplitude and density. caPI3K
1Kcnj2 and Kcnj12 (not assessed with
exercise) (456)
TAC model: caPI3K prevented a 2IK1
current density and 1current amplitude
(456)‡
TASK-1 KCNK3 Ventricle and atria: human and Swim training in mice 1current amplitude
mouse (299) and density, 1TASK1, 1Knk3 (455)
caPI3K: 1current amplitude and density,
1TASK1, 1Kcnk3 (455)
Transgenic model of DCM: no change in
current amplitude or density, 2Kcnk3.
Exercise and caPI3K 1current
amplitude and density. caPI3K 1Kcnk3
(not assessed with exercise) (456)
Kir3.1 KCNJ3 Activated by acetylcholine Knockout mice with loss of function of
Kir3.4 show a delayed recovery of
resting heart rate after exercise (275)
Kir3.4 KCNJ5 Not assessed in Refs. 455, 456
Kir6.2 KCNJ11 Activated by 1[ADP]/[ATP] Short-term treadmill exercise increased
the expression of KATP in the heart
(469)
Not assessed in Refs. 455, 456
Exercise-induced shortening of AP
attenuated in Kir6.2 KO (469)
Depressed cardiac function and
pathological heart growth in Kir6.2 KO
mice subjected to 28 days of moderate
swim training (183)
Treadmill for 11 wk in rats (associated
with 1HW/BW) 1affinity of NCX for
Ca2⫹ (412)
Aerobic interval treadmill training for 6 wk
in mice was associated with 1SERCA2a
protein and function, i.e., 1Ca2⫹ SR
uptake (195). The same protocol was
associated with 1cardiac myocyte
contractility, larger calcium amplitudes,
faster relaxation, phosphorylation of
PLB, and increased activation of
CaMKII␦ (196). Some of these changes
were prevented with a CaMKII inhibitor
(196) (proposed mechanism via CaMKII
phosphorylating PLB).

*Kv4.3 predominant in larger mammals. †Ionic current not assessed in study. ‡Exercise not assessed. For “protein,” the primary ␣-subunit of
the major ion channel is included. Accessory/␤-subunits have not been listed but can be found in References 299, 300. AP, action potential;
BW, body weight; DCM, dilated cardiomyopathy; E-C, excitation-contraction; HW, heart weight; KO, knockout; TAC, transverse aortic constric-
tion. Reference numbers are given in parentheses.

plays a critical role for the acute regulation of Ca2⫹ into the
mitochondria in response to exercise (217).
I) KATP channels. KATP
D) LIGAND-GATED CHANNELS (KATP AND KACh).
channels are considered to play a prominent role in re-
sponse to stress or metabolic challenges including exercise.
The KATP channel is distributed in all regions of the heart
and is considered to link cellular metabolism with mem-
brane excitability. The activity of KATP is regulated by ad-
enine nucleotides, typically being activated by falling ATP
and rising ADP levels (414). Stress-induced opening of the
channel has been considered protective because the opening

Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org 435

 BERNARDO ET AL.
of KATP leads to quicker repolarization, shortening of the
AP, and reduced Ca2⫹ influx. This results in the conserva-
tion of cellular energy stores and prevents calcium overload
(184, 414). The KATP channel in cardiac myocytes is en-
coded largely by Kir6.2 (FIGURE 5C). Kir6.2 KO mice have
been subjected to treadmill stress exercise testing and mod-
erate aerobic swimming exercise (183, 468). Under basal
conditions, cardiac function was comparable in Kir6.2 KO
and wild-type mice. However, Kir6.2 KO mice displayed a
reduced capacity to perform a high-intensity treadmill test
(lower work load and duration), and disruption of cardiac
performance was implicated (468). In response to a 28-day
modest swimming protocol, global Kir6.2 KO mice dis-
played hypertrophy that was associated with depressed sys-
tolic function and myocyte damage (physiological hyper-
trophy not observed in wild-type mice with this exercise
protocol). While these results are confounded by the dele-
tion of Kir6.2 within other organs (e.g., skeletal muscle), it
was reported that KO mice swam to a similar degree to
wild-type mice (confirmed by similar enhancement in skel-
etal muscle aerobic capacity and lower resting heart rates)
(183). Consistent with the KATP channel playing a key role
in the heart in response to exercise, cardiac-specific trans-
genic mice with nonfunctional KATP channels displayed an
attenuated response to short-term exercise. Treadmill exer-
cise at moderate speed for 5 days in wild-type mice was
associated with increased cardiac expression of Kir6.2 and
shortening of the AP in response to an exercise-induced
increase in heart rate. These changes were blunted in the
transgenic mice (469). Thus KATP is considered to be re-
quired for the beneficial cardiac effects of exercise (184).
II) KACh channels. After exercise has ceased, it is important
for the heart rate to return to normal levels within a short
time frame. A delay in heart rate recovery after exercise has
been shown to be an independent predictor of mortality in
healthy individuals as well as those with underlying cardiac
disease (74, 75, 179, 305). Release of acetylcholine from
cardiac vagal nerves is responsible for the heart rate recov-
ery after exercise. Acetylcholine binds to muscarinic recep-
tors in the heart (M2) which are abundant in the atria, SA
node, and AV node. Binding to M2 receptors activates in-
hibitory G proteins (Gi) that 1) inhibit PKA activity and
downstream effects on contractility and 2) promote the
opening of KACh channels (increases in IKACh) (138, 275)
(FIGURE 5C). KO mice with loss of function of Kir3.4, which
encodes an integral subunit of the IKACh channel, show a
delayed recovery of resting heart rate after an acute 5 min
swim or treadmill test (275).
E) LONG-TERM CHANGES TO CARDIAC EXCITABILITY AND E-C COUPLING WITH
PHYSIOLOGICAL CARDIAC HYPERTROPHY AND PROTECTION FROM DIS-
EASE. During exercise, there are acute changes to the conduc-
tion system and E-C coupling to increase heart rate and
contractility. However, with regular long-term exercise and
the development of exercise-induced adaptions including
436 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
physiological hypertrophy, chronic changes are required.
To maintain cardiac excitability in a setting of exercise-
induced cardiac hypertrophy, it is important for the density
of ion channels on cardiac myocytes to increase in parallel
with the increase in cardiac myocyte size. It was shown that
cardiac electrical function was maintained in mice with ex-
ercise-induced hypertrophy due to chronic swim training
for 4 wk or in caPI3K mice with physiological hypertrophy.
ECG traces and AP waveforms were comparable in exercise
and caPI3K mice compared with untrained mice and non-
transgenic mice (recordings made under resting conditions
not during exercise). The comparable ECG traces and APs
were attributed to an increase in repolarizing outward K⫹
current amplitudes together with an increase in inward
Ca2⫹ currents (455). This is in contrast to the prolongation
of the AP which is a common feature of pathological car-
diac hypertrophy and heart failure and can make the heart
susceptible to arrhythmia (163). Exercise training in mice
has also been shown to regulate the protein and gene ex-
pression of a number of channels responsible for currents
highlighted on FIGURE 5 (455) (TABLE 2).
In cardiac disease rodent models, exercise or increased car-
diac PI3K activity has been shown to have favorable out-
comes on electrical activity/AP and E-C coupling. Treadmill
running in rats which began 4 wk post-MI resulted in better
intracellular Ca2⫹ handling and sensitivity within cardiac
myocytes compared with nontrained MI rats (446). Cardiac
disease mouse models including pressure overload-induced
pathological hypertrophy (transverse aortic constriction,
TAC) and dilated cardiomyopathy with heart failure (trans-
genic model) are characterized by QT prolongation, de-
creased K⫹ current densities, and impaired repolarization.
Transgenic expression of caPI3K was able to attenuate or
prevent ECG and AP abnormalities in these disease models,
and protection was associated with increased repolarizing
K⫹ current amplitudes (e.g., IK1, Ito) and increased expres-
sion of K⫹ channel subunits (e.g., Kir2.1, Kir2.2, Kv4.2,
Kv4.3) (456). Swim training for 4 wk also upregulated re-
polarizing K⫹ currents in the model of dilated cardiomyop-
athy and heart failure (456) (TABLE 2).
As de-
F) NO-RELATED MECHANISMS ASSOCIATED WITH E-C COUPLING.
scribed in section IIC1, NO is increased in response to ex-
ercise and has been shown to play a key role for exercise-
induced cardiac protection via vascular adaptations (58,
332). NO derived from eNOS and nNOS within cardiac
myocytes can also regulate numerous steps of E-C coupling
(259) (FIGURE 4B). NO derived from eNOS within the
plasma membrane of cardiac myocytes (e.g., within cave-
olae activated by ␤3-AR or stretch) can potentially regulate
ROS production, myofilament sensitivity, PLB, and RyR2
(251, 372) (FIGURE 4B). Exercise-induced ␤1-AR signaling
results in a positive inotropic effect via cAMP-PKA signal-
ing phosphorylating the L-type Ca2⫹ channel and enhanc-
ing SERCA2a (via the phosphorylation of PLB). It has been
 EXERCISE-INDUCED CARDIAC PROTECTION

suggested that ␤3-AR-induced NO production may blunt
␤-adrenergic inotropic responses in disease settings (58, 59,
372).
NO derived from nNOS in the SR (FIGURE 4B) may also
provide benefit in a setting of exercise by 1) inhibiting Ca2⫹
entering myocytes via the L-type Ca2⫹ channels, 2) stimu-
lating reuptake of Ca2⫹ into the SR by phosphorylating
PLB, 3) modulating ␤-adrenergic inotropic responses, and
4) reducing oxidative stress (372). A favorable effect of
exercise on the balance of ROS and NO in the heart (ni-
troso-redox balance) is thought to contribute to exercise-
induced cardiac protection; attributed to NO “buffering”
ROS (353). nNOS is elevated in the heart in response to
exercise and is reported to be the major NOS responsible
for a positive shift in the nitroso-redox balance in ventric-
ular myocytes. By subjecting NOS1 global KO mice (gene
encoding nNOS) to an 8-wk aerobic interval treadmill
training program, it was shown that nNOS is critical for
exercise-induced physiological cardiac hypertrophy and ex-
ercise-induced antioxidant properties (353, 354). In cardiac
myocytes, exercise was associated with increased nNOS
protein, enhanced myocyte contraction (Ca2⫹ transients),
and increased SR Ca2⫹ cycling (load and release). These
adaptations did not occur in myocytes from NOS1 KO
mice. While it is noted that global NOS1 KO mice may have
reduced exercise capacity due to deletion within skeletal
muscle, the investigators consider this unlikely to have con-
tributed to the phenotype because training intensity was
matched to similar levels in control and KO mice (354).
E. Mitochondrial Adaptations: Energy
Production and Redox Status
Overview: the volume density for mitochondria in the hu-
man and mouse heart has been estimated to represent 23
and 32%, respectively (368). Within cardiac myocytes, mi-
tochondria are located just below the plasma membrane
where they provide ATP to membrane ion pumps, and be-
tween myofibrils where they deliver energy to support con-
traction (12, 144). Mitochondria size and number are reg-
ulated by the process of mitochondria fusing (fusion) and
dividing (fission). A balance of mitochondrial fission/fusion
is critical for mitochondrial functions, and loss of this bal-
ance can lead to cardiac disease. Thus the regulation of
mitochondrial fusion-related proteins (e.g., Mfn2 and
OPA1) and fission-related proteins (DRP1) has been con-
sidered a target for cardiac therapies (100, 368). Studies
have suggested that inhibition of excessive/pathological mi-
tochondrial fission is beneficial in the heart (100), and ex-
ercise has been associated with changes in fusion- and fis-
sion-related proteins. For instance, aerobic interval training
in rats (treadmill for 8 wk) provided protection against
MI-induced impairment of mitochondrial respiratory func-
tion, and exercise prevented the MI-induced decrease in
mitochondrial fusion (Mfn2 and OPA1) and increased fis-
sion (DRP1) (175).
Mitochondria play key roles for energy production (ATP),
redox control (producing and scavenging ROS), calcium
homeostasis, contractility, ion gradients, nuclear gene ex-
pression, and cell fate (survival/cell death). In this section
we have focused on the role of mitochondria for energy
production and redox status. Calcium homeostasis was de-
scribed in section IID and cell fate/survival in section IIF.
1. Mitochondrial energy metabolism
The heart has high energy demands having to continuously
contract to provide oxygen and nutrients to the body. Mi-
tochondria generate ATP through oxidative phosphoryla-
tion, a process which generates ⬎90 –95% of the ATP in the
heart (144, 240). With limited ATP reserves (nearly com-
plete turnover of the ATP stores every 10 s), the heart relies
on a continuous energy supply that can be generated from a
number of substrates including carbohydrates (glucose, lac-
tate, and pyruvate) and noncarbohydrates (fatty acids,
amino acids, and ketones) (38, 171, 240). In the normal
healthy heart under resting conditions, oxygen and fuel sup-
ply is relatively abundant. Fatty acids are the preferred fuel
source (60 – 80%), an energy rich substrate. Glucose and
lactate represent the other major fuel sources under resting
conditions (38, 171) (FIGURE 6). Upon entry of free fatty
acids into the cell, the majority are transported into the
mitochondria and undergo fatty acid oxidation (␤-oxida-
tion). Glucose enters the cell via glucose transporters
(GLUT) and undergoes glycolysis. Glycolysis converts glu-
cose to pyruvate under aerobic conditions (lactate under
anaerobic conditions). Pyruvate is transported into the mi-
tochondria and undergoes oxidation (i.e., glucose oxida-
tion). Both pathways (free fatty acids and glucose) con-

FIGURE 6. Effects of exercise on energy metabolism. During exercise, circulating substrate levels (fatty acids, glucose, and lactate) are
regulated dependent on exercise type (e.g., increased fatty acids with aerobic exercise, increased lactate with anaerobic exercise). Substrates
enter cardiac myocytes via active and passive transport (e.g., fatty acids via CD36, glucose via GLUT4). Fatty acids enter the mitochondria and
are converted to acetyl-CoA via fatty acid oxidation (␤-oxidation). Glucose and lactate are converted to pyruvate and undergo glucose oxidation
and conversion to acetyl-CoA. Acetyl-CoA enters the TCA cycle, and reducing equivalents deliver electrons to the electron transport chain,
leading to ATP generation via oxidative phosphorylation. AMPK, PGC-1␣, and PI3K are increased in the heart in response to exercise and can
regulate components of energy metabolism by affecting fatty acid oxidation and gene expression. PGC-1␣ is an important transcription
coactivator; when in combination with other transcription factors (TF), it regulates the expression of genes related to fatty acid oxidation and
mitochondrial biogenesis.

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 BERNARDO ET AL.

Fatty acids Lactate Glucose

Circulation
CD36 GLUT4

Cardiomyocyte
AMPK AMPK
<5% ATP

EXERCISE Fatty acids

Glycolysis DISEASE
Inadequate
PGC-1α glucose oxidation
Lactate Pyruvate
+
PI3K + +
AMPK +
↑ Proton production

Mitochondria

Fatty acid Glucose

oxidation Acetyl- oxidation
CoA

ATP
e-
TCA e- e-
cycle
>95% ATP
AMPK e-

EXERCISE
Electron transport chain Cardiac contraction

PGC-1α
Oxidative phosphorylation

Nucleus PGC-1α
Fatty acid oxidation Glycolytic
PPARα genes PPARγ genes

PGC-1α
Fatty acid oxidation genes
TF Mitochondrial biogenesis
TCA

EXERCISE DISEASED HEART

↔ / ↑ Fatty acid oxidation ↔ / ↓ Fatty acid oxidation

↔ / ↑ glucose oxidation: glycolysis ↓ glucose oxidation: glycolysis
↑ ATP ↓ ATP
↑ proton production
↑ efficiency ↓ efficiency

438 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org

 EXERCISE-INDUCED CARDIAC PROTECTION
verge to produce acetyl-CoA which undergoes oxidation
in the TCA cycle and the production of ATP (via reducing
equivalents, delivery of electrons to the electron trans-
port chain, and generation of a proton gradient across
the inner mitochondrial membrane) (171, 240, 395). The
balance of fatty acid oxidation, glucose oxidation, and
glycolysis has an impact on cardiac efficiency and energy
production (FIGURE 6).
During exercise, energy expenditure of the heart increases
severalfold compared with resting conditions. This is asso-
ciated with a rise in oxygen consumption and an increased
rate of mitochondrial ATP production that matches the rate
of ATP breakdown by the working muscles (12). It is gen-
erally accepted that the metabolic phenotype of the exer-
cise-trained heart and diseased heart are different (FIGURE
6). While varying views exist regarding the key metabolic
changes that occur in each state, which may differ depend-
ing on disease or exercise type and/or duration, some com-
mon findings are emerging. In the diseased heart, one long-
standing view has been that the heart becomes energetically
starved due to inadequate rates of energy substrate metab-
olism and ATP production. A more recent view is that the
chronically stressed heart uses energy inefficiently due to
mismatched glucose metabolism (i.e., where glycolysis is
uncoupled from glucose oxidation). Mismatched glucose
metabolism causes accelerated proton production that can
lead to acidosis and impaired myocyte contractility (171,
258) (FIGURE 6). Lopaschuk and colleagues (258) demon-
strated that in the failing mouse heart due to MI, the hearts
were inefficient in energy utilization for mechanical func-
tion, i.e., mismatch in glucose metabolism due to alterations
in glucose oxidation not matching the changes in glycolysis.
As in the diseased heart, the effect of acute and endurance
exercise on cardiac metabolism requires further study
(427). However, in contrast to a disease setting, there is
evidence to suggest that exercise is associated with en-
hanced fatty acid and glucose oxidation in the heart or no
significant change (FIGURE 6) (427). In healthy trained male
subjects, myocardial oxidation of exogenous glucose in-
creased during moderate-intensity exercise (cycle ergometer
exercise at 40% of the subject’s maximal O2 uptake 25–50
min) (133). The increased use of glucose with exercise has
been considered a more efficient energy source than fatty
acids (producing more ATP per O2 molecules consumed)
(121, 427). There is also a high use of fatty acids during
exercise as a result of elevated circulating triglycerides and
free fatty acids due to increased lipolysis in adipose tissue.
Treadmill exercise in female rats (10 wk, 4 days/week) was
associated with cardiac hypertrophy, lower rates of glycol-
ysis, higher glucose oxidation, and higher rates of fatty acid
oxidation. Rats subjected to this training protocol were also
protected against ischemia-reperfusion injury (improved re-
covery of function associated with lower glycolysis, and
higher fatty acid oxidation) (53). Thus it was concluded
that exercise induces a protective metabolic phenotype that
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
protects the heart in settings of cardiac stress. One expla-
nation for the improved outcome in cardiac stress settings is
the lower net proton production of glucose oxidation com-
pared with glucose fermentation (glycolysis and reoxida-
tion of NADH produced by glycolysis). Lower proton pro-
duction is associated with better recovery of intracellular
pH which would be expected to limit calcium overload
(H⫹/Na⫹ and Na⫹/Ca2⫹ exchange) and reduce the ener-
getic cost of maintaining ion homeostasis (53). Higher fatty
acid oxidation in the exercise-trained heart may also help
limit the toxic effects of high free fatty acids on the cytosol
and mitochondria (53). In another study, swim exercise
training for 3 wk in mice before acute MI was associated
with reduced infarct size, and exercise prevented the MI-in-
duced decrease in fatty acid metabolism-related genes [e.g.,
those encoding carnitine palmitoyltransferase 1 (CPT-1), me-
dium chain acyl-CoA dehydrogenase (MCAD), peroxisome
proliferator-activated receptor ␣ and ␥ (PPAR-␣ and -␥)]
(405).
Substrate availability is one key factor which “dictates” the
choice of substrate used by the heart to produce energy, but
other mechanisms include the activation of kinases/signal-
ing cascades [e.g., PI3K, AMPK, and proliferator-activated
receptor ␥ co-activator 1␣ (PGC-1␣)] and transcriptional
regulation of genes involved in metabolism. The PPAR fam-
ily of transcription factors (PPAR-␣ and PPAR-␥) regulate
the expression of genes encoding enzymes of fatty acid and
glucose metabolism. Models of chronic exercise training in
rodents (e.g., swim training or treadmill) have been shown
to increase AMPK, PGC-1␣, and PI3K in the heart and
promote fatty acid oxidation, ATP generation, and mito-
chondrial biogenesis (2) (FIGURE 6). AMPK is considered
beneficial by increasing fatty acid uptake and oxidation,
accelerating glucose uptake via translocation of GLUT4 to
the plasma membrane, and inhibiting energy-consuming
pathways (e.g., protein synthesis) (101). The critical role of
PI3K for mitochondrial adaptations was demonstrated us-
ing mice with decreased cardiac PI3K activity (dnPI3K
mice). In response to chronic swim training, dnPI3K mice
did not display an exercise-induced increase in mitochon-
drial ATP production and fatty acid oxidation (310). IRS1
and IRS2 also play critical roles for chronic swim exercise-
induced mitochondrial adaptations (e.g., measures of mito-
chondrial fatty acid metabolism) (310, 347). In contrast,
Akt and PDK1 do not appear to play an essential role for
chronic swim exercise-induced mitochondrial adaptations
(307, 310).
Of note, this section has focused on the production of ATP
generated from fatty acids and glucose because these are
considered the main substrates during aerobic exercise.
However, during intense anaerobic exercise, lactate con-
centrations in the blood rise, and the heart predominantly
uses lactate (240). In addition, while fatty acids and carbo-
hydrates have been considered the key substrates for car-
439
 BERNARDO ET AL.
diac ATP production, it is now emerging that ketones and
branched chain amino acids can play an important role in
contributing to energy production in some settings such as
heart failure and can compete for acetyl-CoA (244). To
date, the significance of these substrates for the heart in a
setting of exercise is less clear, but it is noteworthy that
ketone bodies are oxidized as a fuel source during exercise
and can act as signaling metabolites (114).
2. Redox control
Oxidative stress is a term typically used to describe elevated
intracellular levels of ROS due to an imbalance between free
radicals, ROS, and antioxidants which contribute to pa-
thology by causing damage to DNA, proteins, and lipids
(369). ROS can be produced from a number of sites includ-
ing the cytosol, plasma membrane, nucleus, and peroxi-
somes. However, in cardiac myocytes, mitochondria are
considered the predominant source of ROS. Under normal/
basal conditions, ROS are produced as byproducts of mito-
chondrial electron transfer activity and are buffered by an-
tioxidant systems. These “physiological” ROS act as signal-
ing molecules to regulate physiological processes (7, 357,
369). In cardiac disease settings, chronic elevation of ROS
can lead to mitochondrial dysfunction, cell death, inflam-
mation, and fibrosis (357). However, elevated ROS in re-
sponse to exercise can have beneficial effects in the heart (7,
357, 369). The distinct outcomes appear to be dependent on
the exposure time to ROS (e.g., persistent vs. pulsatile), the
proximity of ROS to moieties most susceptible to damage,
and the capacity of the endogenous cellular ROS scavenging
mechanisms (i.e., antioxidant capacity). Exercise is associ-
ated with pulsatile, compensated oxidative stress (e.g., aug-
mentation of antioxidant capacity), whereas disease is as-
sociated with persistent and uncompensated oxidative
stress (i.e., the endogenous protective mechanisms are over-
whelmed) (7). Excessive ROS is also known to activate
signaling cascades associated with cardiac disease including
chronic CaMKII activation (112).
Exercise-induced mechanical loading/stretch of the heart,
as well as neurohumoral activation, has been implicated for
increasing ROS generation and the subsequent upregula-
tion of antioxidant defense mechanisms in the recovery
phase (e.g., glutathione reductase, thioredoxin reductase,
and manganese superoxide dismutase) (7, 159). ROS act-
ing as second messengers to alter redox-sensitive enzymes
is considered to contribute to exercise-induced adaptive
signaling. Adaptive responses to ROS also include mito-
chondrial adaptations (e.g., increased biogenesis, en-
hanced mitochondrial phosphorylation capacity and ef-
ficiency) and activity of cell quality control systems (e.g.,
autophagy/mitophagy; discussed in further detail in sec-
tion IIF3A) (7).
Of note, while ROS is elevated intermittently with exercise,
basal ROS levels have been shown to be reduced in cardiac
440 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
myocytes from mice subjected to 8 wk of aerobic treadmill
interval training compared with untrained mice (353).
Treadmill running for 10 days in rats was reported to pro-
tect against arrhythmia by better maintaining the mito-
chondrial membrane potential, lowering mitochondrial
ROS production, and preserving redox homeostasis (8).
Mice with chronic elevation of PI3K in the heart (caPI3K
mice) were protected against maladaptive ROS in a setting
of diabetic cardiomyopathy (349). Finally, as described in
section IID1F, an 8-wk aerobic interval treadmill training
program in mice increased NO which is thought to buffer
excess ROS in settings of cardiac pathology (353, 354).
F. Cellular Stress Responses: Survival and
Death
Since the majority of adult cardiac myocytes are unable to
proliferate or be renewed (331, 390, 391), systems to pro-
mote myocyte survival and prevent cell death are critical for
maintaining cardiac function. Cells have a number of sys-
tems/strategies to maintain normal physiological functions
and to monitor and cope in conditions of stress including 1)
heat shock response, 2) ubiquitin-proteasome system, and
3) organelle-specific stress responses [e.g., mitochondria,
endoplasmic reticulum (ER), autophagic-lysosomal path-
way, nuclear DNA response] (211) (FIGURE 7). Many of
these systems work together to form a multilayered system
to protect against pathological insults. Exposure to a mild/
intermittent stress such as exercise has been shown to acti-
vate a number of stress responses that are considered to
better prepare the cell against stronger/chronic stress stim-
uli (as may occur in a cardiac disease setting). Thus the
maintenance of mechanisms for counterbalancing stress is
considered a potential strategy for preventing cell death and
pathology (160, 211).
1. Heat shock response
Heat shock proteins (Hsps) are molecular chaperones that
contribute to a number of protein quality control mecha-
nisms including the folding of newly synthesized proteins,
and the clearance/removal of misfolded proteins and aggre-
gates (47, 160). In a setting of increased misfolded proteins,
refolding by Hsps and co-chaperones is considered the pref-
erential response. However, if the protein cannot be re-
folded to its native form, it can be degraded by the ubiquitin
proteasome system (UPS), a process also involving chaper-
ones and co-chaperones (FIGURE 7). If the chaperone and/or
UPS machineries become rate limiting, misfolded proteins
are likely to aggregate and can be removed via the process of
autophagy (381). The Hsp70 family, and in particular the
inducible form of Hsp70, is considered primarily responsi-
ble for the protective effects of the Hsp response induced by
exercise. Hsp70 is rapidly upregulated in response to cellu-
lar stresses, such as heat, oxidative stress, alterations in pH,
and increased Ca2⫹, many of which occur in response to
 EXERCISE-INDUCED CARDIAC PROTECTION

HEAT SHOCK
RESPONSE
Protein
synthesis AUTOPHAGY
Cathepsins Lysosome LYSOSOMAL DEGRADATION
Beclin 1
Protein Vps34 Bcl-2 EXERCISE
Hsp70 EXERCISE
folding

Cellular Cellular
Beclin 1
p62

7 Atg5
stress p62 p62 p62
stress Ub
Ub Ub
-II
Ub
-II
Ub ↑ Protein
LC3
Ub Ub
LC3 LC3
Ub Ub Ub Ub
Ub Ub
Ub Ub Ub
Degradation

A tg
Native Misfolded Protein
protein protein aggregate
Hsp70 MACROAUTOPHAGY Autophagosome LAMP-2A
Protein
E3 ligases Ub
refolding Hsp70 Ub
Ub
eg. CHIP HSF1 Ub ± E3:CHIP
HSPs
Nucleus
Hsc70
HSF1 MITOPHAGY + complex
HSP70 ATF(N)
Chaperones
HSPs Activated e.g. BiP
HSF1
Misfolded
HSPs XBP1s Chaperones protein
ER homeostasis
CHAPERONE-MEDIATED
EXERCISE ATF4 Chaperones AUTOPHAGY
FOXO Inhibition XBP1
of growth Antioxidants
Ub CHOP
Ub E3 ligases FOXO
Ub ATF(N)
Ub DNA
Hsp70 MAFbx K63 Golgi
Telomere
DAMAGE XBP1s Apparatus
E3 ligases MAFbx K48 dysfunction
MuRF1 ATF4
DNA damage
ROS Spliced ATF6
P BiP
eIF2α P
BiP
mPTP opening ↓ Protein IRE1
synthesis BiP
P
EXERCISE PERK BiP
Degradation BiP
26S Proteasome Mild UPR ER
BiP
Protective
UBIQUITIN- ER STRESS
Disease
PROTEASOME MITOCHONDRIA UNFOLDED PROTEIN
induced UPR
SYSTEM EXERCISE RESPONSE

FIGURE 7. Effects of exercise on stress response pathways in the heart. Exercise is able to regulate
components of the 1) heat shock response, 2) ubiquitin-proteasome system, 3) autophagy lysosomal degra-
dation, 4) the opening of the mPTP in mitochondria, 5) ER stress unfolded protein response, and 6) the DNA
damage response. Due to the complex nature of each process and multiple interactions between processes,
only those most relevant to exercise are shown.

exercise (202). Numerous studies have shown that exercise improvements in functional recovery in isolated rat hearts
upregulates Hsp70 in the rodent heart, in some cases in an subjected to ischemia-reperfusion injury (320). However,
intensity-dependent manner, and in response to acute and rats trained in the cold to prevent the induction of Hsp70
long-term exercise adaptations (67, 94, 160, 194, 276, 306, displayed a similar degree of cardioprotection to rats
406). Exercise-induced increases in myocardial Hsp70 con- trained in ambient temperatures in ex vivo and in vivo mod-
tent appear to occur primarily in response to the exercise- els of ischemia-reperfusion injury (340, 406). Furthermore,
induced increase in core body temperature, as there was no Hsp70 is not required for PI3K(p110␣)-induced cardiac
upregulation of Hsp70 in the hearts of rats trained in the protection, yet PI3K(p110␣) is a critical regulator of exer-
cold (148, 152, 406). Expression of Hsp70 is regulated by cise-induced hypertrophy and protection (434).
the transcription factor heat shock factor 1 (HSF1). Under
basal conditions, HSF1 is in an inactive form in the cyto- 2. Ubiquitin-proteasome system
plasm in a complex with Hsp70 and other Hsps. In the
presence of cellular stress, misfolded proteins competitively The UPS plays a major role for the routine turnover of
bind Hsps, and HSF1 is released from the complex. HSF1 proteins and the degradation of damaged proteins (211).
then translocates to the nucleus where it binds to heat shock The accumulation of damaged/misfolded proteins, referred
elements and upregulates the expression of Hsps including to as proteotoxicity, has an adverse effect on organelles and
Hsp70 (444) (FIGURE 7). cells. Proteotoxicity has been implicated in settings of car-
diac pathology, and dysfunction of the UPS has been re-
There is a large body of evidence suggesting that Hsp70 is ported in settings of human cardiomyopathy (86, 430).
critical for mediating protection in acute cardiac stress set- The UPS is responsible for degrading ~90% of proteins in
tings (444). However, the role of Hsp70 in chronic cardiac the majority of mammalian cells, within multiple com-
disease settings (34) and exercise is less clear. Silencing of partments (cytoplasm, nucleus, ER). UPS-induced pro-
Hsp70 with oligonucleotides attenuated exercise-induced tein degradation typically consists of two steps. First, a

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 BERNARDO ET AL.
protein is tagged with a polyubiquitin chain (four or
more ubiquitin molecules), a step involving three en-
zymes: 1) ubiquitin-activation enzyme (E1), 2) ubiquitin-
conjugating enzyme (E2), and 3) ubiquitin ligase (E3)
(270, 318, 420). Second, the tagged protein is degraded
by the proteasome (a large multisubunit protease com-
plex, 26S) (FIGURE 7). The proteasome is primarily a
cytosolic enzyme but is also located in nuclei and the ER
membrane. In most cases, chains of polyubiquitin are
linked to the targeted protein through lysine 48 (K48;
“canonical” ubiquitination). However, linkage can also
occur with other lysine residues such as lysine 63 (K63;
“noncanonical” ubiquitination). As described below,
ubiquitination also has roles independent of the protea-
some including the regulation of transcription factors,
gene transcription, and autophagy (270).
Hundreds of distinct E3 ligases have been identified, but
only a relatively small number have been found to be muscle
specific (heart and skeletal muscle) (270). The role of the
UPS in a setting of cardiac hypertrophy (exercise- or dis-
ease-induced) is not well understood, but it has been shown
that both protein synthesis and UPS-controlled protein deg-
radation are elevated in the hypertrophied heart (318). At
least two muscle-specific E3 ligases have been shown to be
regulated in the heart with exercise, i.e., muscle atrophy
F-box (MAFbx, also known as atrogin-1) and muscle RING
finger protein 1 (MuRF1) (5, 270, 318). With the use of
genetic mouse models, it was shown that MAFbx inhibits
exercise- and IGF1-induced cardiac growth via the activa-
tion of Forkhead box transcription factors (Foxo1 and
Foxo3a) (231). A mechanism involving the ubiquitination
of K63 polyubiquitin chains and the regulation of transcrip-
tion rather than degradation by the proteasome was re-
ported (231, 318) (FIGURE 7).
3. Organelle-specific stress responses
A) AUTOPHAGY-LYSOSOMAL DEGRADATION PATHWAY. In addition to
the proteasome, the lysosomal system is the other main
system responsible for the turnover of proteins. In contrast
to the proteasome system which selectively degrades nor-
mal proteins (typically with short half-lives) and abnormal
proteins, the autophagic-lysosomal pathway is considered
the main mechanism responsible for the degradation of pro-
teins with longer half-lives. The lysosomal system is also
able to degrade whole organelles (e.g., mitophagy) and
large protein aggregates (167, 211, 304) (FIGURE 7). Three
types of autophagy have been described based on the lyso-
somal delivery system: 1) macroautophagy [involving fu-
sion of an autophagosome (a double membrane vesicle with
sequestered damaged proteins/cytoplasmic materials/or-
ganelles) with a lysosome to form an autolysosome, fol-
lowed by digestion of the material], 2) microautophagy (ly-
sosome directly engulfs cytosolic components), and 3)
chaperone-mediated autophagy [requires unfolding of the
protein and internalization into the lysosome for degra-
442 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
dation and involves heat shock cognate protein 70
(Hsc70) and lysosomal membrane-bound lysosomal-as-
sociated membrane protein 2A (LAMP2a)] (211, 430)
(FIGURE 7; microautophagy not presented). Most cardiac
research has focused on macroautophagy, and this has
typically been referred to as “autophagy” (430).
Under basal conditions, autophagy functions as an intracel-
lular recycling system for protein and organelle quality con-
trol and is required for cardiac myocyte function and sur-
vival. Deletion of autophagy specific genes (Atgs; e.g., Atg5)
led to pathological cardiac hypertrophy and dysfunction in
mice (295, 404). In response to cellular stress, autophagy
levels increase, and this process of degrading proteins is
accompanied by the release of energy, permitting cells to
adapt to changing nutritional and energy demands (156).
Macroautophagy is considered to play a key role for de-
grading aberrant protein aggregates and organelles in car-
diac myocytes under disease settings (430). Fewer studies
have explored the role of autophagy in the exercise-trained
heart. However, a key study from He et al. (156), utilizing
mice that transgenically express a green fluorescent protein
(GFP)-labeled marker of autophagasomes (LC3), demon-
strated that autophagy also plays an important role in the
heart in response to exercise. It was shown that treadmill
exercise-induced autophagy in the heart in vivo within 30
min, and this was associated with conversion of LC3-I to
LC3-II (autophagosome-membrane-associated form of
LC3), and degradation of p62 (autophagy substrate pro-
tein). It was also shown that exercise-induced disruption of
the Bcl-2-beclin 1 complex is essential for exercise-induced
autophagy in the heart; Bcl-2 is an anti-autophagy protein
that inhibits autophagy by direct interaction with beclin 1
(FIGURE 7). Mutant mice with normal levels of basal au-
tophagy but deficient in exercise-induced autophagy (due to
mutations in the phosphorylation sites of Bcl-2) displayed
lower maximal exercise capacity (baseline skeletal muscle
strength and cardiac function were normal) (156). It was
not directly assessed whether this was due to defects in
skeletal muscle, heart, or both. Other studies in exercise-
trained rodents have also reported an increase in au-
tophagy-related and -regulatory genes (e.g., LC3-II, p62,
Bcl-2) in cardiac muscle (312, 402). In addition, Chen et al.
(65) showed a link between autophagy of proteins in the
heart and exercise-induced cardiac protection in rabbits
with MI.
The carboxy terminus of Hsp70-interacting protein (CHIP)
regulates a number of quality control pathways and can
also affect exercise-induced autophagy. CHIP is a co-chap-
erone that interacts with Hsp70 to mediate refolding, and
also acts as a ubiquitin ligase (E3 Ub ligase) (444). More
recently, CHIP was shown to regulate autophagy via a pro-
cess termed “chaperone-assisted autophagy” which is ubiq-
uitin-dependent (different from chaperone-mediated au-
tophagy which is ubiquitin-independent) (FIGURE 7). The
 EXERCISE-INDUCED CARDIAC PROTECTION
role of CHIP was assessed by subjecting CHIP KO mice to
5 wk of voluntary wheel running. In hearts of wild-type
mice, there was no significant effect on autophagy-related
genes (e.g., Atg7, Atg5, Vps34). However, each of these
genes was elevated in hearts from running CHIP KO mice
(no change in sedentary mice). After 1 wk of running, CHIP
KO mice were reported to have increased autophagic flux
(based on LC3BII/LC3BI ratio after 1 wk), and LAMP2a
and cathepsin L expression were elevated after 5 wk. There
was no significant increase in autophagy regulators in wild-
type mice, but there was a trend for an increase in LC3BII
and LAMP2a. CHIP KO mice also displayed an exagger-
ated hypertrophic response to wheel running compared
with wild-type mice, but this was not associated with mark-
ers of pathology (e.g., no evidence of fibrosis and cardiac
function was normal; mild nonsignificant increase in ANP)
(443). The enhanced physiological response in the KO was
attributed to loss of CHIP being associated with enhanced
IGF1-Akt signaling and increased autophagic flux. The in-
vestigators speculate that enhanced autophagy in CHIP KO
mice after running wheel exercise would allow misfolded
proteins and/or mitochondria that accumulate during run-
ning to be cleared. However, interpretation of this study is
complex because the CHIP KO have increased misfolded
proteins under basal conditions and are more susceptible to
MI (278, 461). The authors note that the increase in au-
tophagy in running CHIP KO could be due to a compensa-
tory mechanism to decrease the burden of unfolded/
damaged proteins, or CHIP inhibiting autophagy. Hsc70 is
critical for the chaperone function of CHIP as well as chap-
erone-mediated autophagy. Thus it is possible that when
CHIP is present, it targets Hsc70 for ubiquitination and
proteasomal degradation, limiting its availability for au-
tophagy. While the mechanism will require further exami-
nation, it appears CHIP regulates autophagy in response to
exercise (443).
Preliminary data suggest that defective autophagy (due to
deletion of Atg7) leads to a maladaptive cardiac phenotype
in response to voluntary wheel running in a setting of met-
abolic stress (obesity and insulin resistance). Premature
death occurred in 40% of heart and skeletal muscle-specific
Atg7 KO mice that had been placed on a high-fat diet for 12
wk and subjected to voluntary wheel running. Death was
attributed to cardiomyopathy associated with cardiac en-
largement and fibrosis (238).
Finally, when considering upstream mechanisms regulating
autophagy, it is noteworthy that autophagy is controlled by
mTOR which is regulated by growth factors including IGF1
which are released from the heart in response to exercise
(301). Collectively, the studies above highlight the complex
interactions between protein quality control mechanisms
within the heart, and further work will be required to un-
derstand how exercise regulates these processes.
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
B) MITOCHONDRIA. Mitochondria can respond to a variety of
stress signals (e.g., oxidative stress, hypoxia, loss of growth
factors, and DNA damage) and are able to switch on a cell
death program (necrosis or apoptosis) by opening of the
mitochondrial permeability transition pore (mPTP; located
in the inner mitochondrial membrane; FIGURE 7). Under
normal healthy conditions, the inner mitochondrial mem-
brane is largely impermeable, only allowing equilibration of
ions and water and small molecules. This regulation allows
mitochondria to maintain a pH gradient and membrane
potential which drives oxidative phosphorylation. In set-
tings of stress, opening of the mPTP causes collapse of the
membrane potential, swelling of the mitochondria, and cell
death (144). It has been suggested that acute exercise (60
min treadmill bout) and chronic exercise (5 wk treadmill
running) have the capacity to decrease mPTP induction/
opening and apoptotic signaling in settings of cellular or in
vivo cardiac stress (e.g., doxorubicin-treated rats). In these
studies, mitochondrial swelling, mitochondrial function,
and/or protein expression of apoptotic and mPTP-related
proteins were assessed (11, 250).
C) ENDOPLASMIC RETICULUM AND UNFOLDED PROTEIN RESPONSE. The en-
doplasmic reticulum (ER) controls the synthesis, folding,
and assembly of proteins before trafficking in vesicles to the
Golgi apparatus, cytosol, and plasma membrane. Only cor-
rectly folded proteins are transported out of the ER. Short-
term ER stress (as may occur with acute exercise) will trig-
ger the unfolded protein response (UPR) which is initially
considered adaptive because it involves transduction events
which eliminate misfolded proteins and restores ER homeo-
stasis. However, with prolonged ER stress, the UPR can
lead to cell dysfunction and cell death. The ER stress re-
sponse begins with the ER chaperone [ER-specific HSP70
family member: glucose-regulated protein kinase 78
(Grp78)/BiP] sensing unfolded or damaged proteins and
dissociating from three UPR sensors: 1) inositol requiring
element-1(IRE-1), 2) PKR-like ER kinase (PERK), and 3)
activating transcription factor 6 (ATF6) (FIGURE 7). This is
followed by the activation of pathways to reestablish ER
homeostasis by inhibiting protein synthesis and increasing
the capacity of the ER (protein folding and degradation).
PERK activation reduces protein synthesis from further
overwhelming the ER via the inactivation of eukaryotic
translation initiation factor 2␣ (eIF2␣). Activated ATF6
shuttles to the Golgi, is cleaved into an active transcription
factor which enters the nucleus, and upregulates the tran-
scription of ER chaperone proteins including Grp78/BiP.
Activation of IRE-1 leads to splicing and activation of X-
box-binding protein 1 (XBP-1), and ultimately increased
expression of genes involved in ER homeostasis. However,
with prolonged ER stress, the UPR can lead to cell dysfunc-
tion and cell death via activation of CHOP (a transcription
factor of the C/EBP family) and caspase pathway (211, 241,
279).
443
 BERNARDO ET AL.
Heart disease is associated with a defective ER stress re-
sponse (142, 143, 235). Cardiac-disease-associated mito-
chondrial dysfunction, calcium imbalance, and oxidative
stress disrupt proper protein folding, resulting in the accu-
mulation of misfolded proteins in the ER. One group re-
ported that short-term exercise (5 days of aerobic treadmill
running) had no effect on ER stress adaptation in rats sub-
jected to ischemia-reperfusion (based on the assessment of
protein expression) (293). More recently, there have been
reports to suggest that exercise can blunt ER stress in a
setting of ischemia-reperfusion or MI (45, 46). In rats sub-
jected to moderate-intensity treadmill running (60 min, 5
days/week for 8 wk) 4 wk post-MI, cardiac function tended
to be better compared with untrained MI rats, and this was
associated with lower expression of UPR markers (e.g., BiP
and CHOP which were elevated with MI) and lower mis-
folded protein (46). In another study, intermittent hypoxia
for 3 wk induced proapoptotic ER stress in the heart includ-
ing higher BiP, pPERK, ATF4, a trend for elevated CHOP
and higher cleaved caspase-3. High-intensity exercise on a
treadmill for 10 days during the last 2 wk of hypoxia was
associated with prevention of these proapoptotic ER stress
markers and reduced ischemia-reperfusion-induced infarct
size (45). In that study, exercise alone seemed to induce a
mild UPR including an increase in BiP and trends for higher
pPERK and ATF4. However, this was not associated with
an increase in CHOP or cleaved caspase-3. Futhermore, in
both studies only associations between exercise and ER
stress in the heart were presented (i.e., no direct evidence of
cause and effect). Studies in genetic mice specifically target-
ing components of ER stress will be required to assess the
precise role of ER stress and exercise-induced cardiac pro-
tection. For instance, utilizing ATF6 KO mice, it was shown
that the UPR plays an important role in mediating the ad-
aptation to exercise in skeletal muscle (450). In summary,
an exercise-induced mild UPR may provide protection by
upregulating defense mechanisms which better prepare the
heart to respond to a more severe disease-induced chronic
UPR.
D) NUCLEAR DNA RESPONSE-TELOMERE SHORTENING. Cardiac disease
and aging are associated with increased ROS that can cause
DNA damage (FIGURE 7). As described earlier, exercise can
attenuate disease-induced ROS. Telomere shortening is also
known to contribute to the DNA damage response. Telo-
meres are DNA-protein structures at chromosome ends.
These sequences protect chromosomal DNA from degrada-
tion and shorten with each cell division (377). Shortening of
telomeres has been associated with a range of age-related
diseases including cardiovascular disease. Several studies
have shown that chronic exposure to exercise is associated
with telomere length maintenance (161, 246). Voluntary
wheel running for 21 days in mice was shown to decrease
markers of cellular aging, upregulate cardiac telomerase
activity, and increase telomere-stabilizing proteins in the
heart. These exercise-induced changes were absent in eNOS
444 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
KO mice, and treatment with IGF1 and growth hormone
upregulated myocardial telomerase activity and increased
pAkt (438). Thus it was concluded that exercise-induced
telomerase activity was mediated by IGF1, Akt, and eNOS.
In another study, cardiac telomere length decreased with
age in the developing rat heart, and this was associated with
an increase in miR-34a gene expression (254), a PI3K-reg-
ulated miRNA (236) (see sect. IIIA2C).
4. Cell death
When cellular stress responses are inadequate, cell death
will occur. Within the heart, cell death can occur via apo-
ptosis, necrosis, and potentially autophagy (FIGURE 8).
There is also growing evidence of crosstalk between au-
tophagy, apoptosis, and necrosis (294). Of these, apoptosis
has been best characterized in the heart in response to ex-
ercise. In the rodent heart, exercise (e.g., voluntary or tread-
mill running ranging from 3 wk to 6 mo) has been accom-
panied by unchanged or decreased levels/rates of apoptotic
markers (176, 386, 438). Exercise training for 12 wk was
shown to attenuate age-induced cardiac apoptosis
(TUNEL) in rats, and this was associated with lower protein
expression of some components of the death-receptor-
dependent apoptotic pathway (extrinsic; FADD, caspase-8,
caspase-3) and the mitochondria-dependent apoptotic
pathway (intrinsic; caspase-9, caspase-3) (219) (FIGURE 8).
PI3K-Akt signaling has also been shown to mediate protec-
tion by preserving mitochondrial integrity and function,
and inhibiting apoptotic pathways (144). In a study in aged
rats, it was suggested that swim exercise (5 times/week for
12 wk) attenuates apoptosis via increasing SIRT1-PGC-1␣
signaling and replaces IGF1-PI3K-Akt signaling. However,
components of the IGF1-PI3K-Akt pathway remained ele-
vated in aged mice with exercise. Thus this conclusion is
somewhat questionable and relies on protein expression
data alone (219).
There is evidence for substantial crosstalk between au-
tophagy and apoptosis (294) (FIGURE 8). For instance, the
interaction between Bcl-2 (anti-apoptotic protein) and be-
clin 1 (autophagy protein) allows for a switch between au-
tophagy and apoptosis. When there is less interaction be-
tween Bcl-2 and beclin 1 (e.g., in response to exercise),
autophagy will increase (156). Caspase-3 can inhibit au-
tophagy by cleaving beclin 1, and caspase-9 is reported to
promote autophagy by a mechanism involving Atg7 and
LC3-II (232).
G. Maintenance of the ECM and the
Antifibrotic Properties of Exercise
The ECM in the heart provides a highly organized struc-
tural framework surrounding cardiac myocytes, allowing
for the coordination of mechanical, electrical, and chemical
processes so that cardiac myocytes contract in a coordi-
 EXERCISE-INDUCED CARDIAC PROTECTION

IGF1
Death
EXTRINSIC receptor

IGF1R NECROSIS
Cytoplasm Opening
or
of mPTP FADD
APOPTOSIS
Caspase-8
EXERCISE
mPTP
PI3K Akt EXERCISE

ROS
INTRINSIC
Bax Bax
Apoptotic Bak
Beclin 1 signal
Bcl-2
Outer mitochondrial membrane
permeabilisation

EXERCISE Bcl-2
Cytochrome C
Beclin 1 Bcl-2
Caspase
activation

Beclin 1
EXERCISE Caspase-9

AUTOPHAGY
EXERCISE Caspase-3

APOPTOSIS
FIGURE 8. Effects of exercise on cell death pathways in the heart. Exercise regulates key players of cell death
pathways (intrinsic/extrinsic apoptosis, necrosis, and autophagy). Each pathway is distinct in their own cellular
processes, but there is crosstalk between apoptosis and autophagy. Akt (downstream of PI3K) phosphorylates
and inhibits the pro-apoptotic factor Bax. Due to the complexities of cell death pathways, only those relevant to
exercise are depicted.

nated way resulting in a uniform and regular cardiac con-
traction (108, 256, 423). The ECM consists of collagens,
glycoproteins (e.g., fibronectin, laminin, elastin), proteogly-
cans, extracellular proteases, and ECM receptors. In the
normal healthy heart, collagens are the most abundant
structural components of the ECM and are produced
mainly by fibroblasts. Previous studies had suggested that
fibroblasts account for as much as two-thirds of the total
cell population in the heart (108, 215, 256, 423). However,
a more recent study using improved tools and markers sug-
gests that fibroblasts account for closer to 11% of the cells
in the heart (328). Balance of the ECM via collagen ECM
synthesis and degradation is critical for maintaining cardiac
function. This is achieved by matrix metalloproteinases
(MMPs) which are enzymes that degrade ECM proteins and
tissue inhibitors of metalloproteinases (TIMPs) which pre-
vent excessive ECM degradation by MMPs. The ECM,
MMPs, and TIMPs can be regulated by numerous factors
and mechanisms including cytokines and growth factors
[e.g., tumor necrosis factor-␣ (TNF-␣), TGF-␤, angiotensin
II, endothelin], inflammatory signaling, the adrenergic sys-
tem, and crosstalk between cardiac myocytes and fibro-
blasts (direct interactions, paracrine and mechano-electric
mechanisms) (215, 256, 416, 423).
A common feature of the diseased heart and pathological
cardiac hypertrophy is cardiac fibrosis, i.e., excessive depo-
sition of ECM proteins by cardiac fibroblasts. Fibrosis
within the heart and other organs is considered one of the
most serious health problems in current medicine (356,
407). In the heart, cardiac fibrosis leads to cardiac stiffen-
ing, impaired electrical conductivity, and cardiac dysfunc-
tion that can lead to arrhythmia and heart failure (416).
Myofibroblasts (smooth muscle-like fibroblasts) in the dis-
eased heart are considered key players responsible for car-
diac fibrosis. In contrast, appreciable expression of myofi-
broblast markers has not been detected in normal healthy
adult hearts (215). Myofibroblasts can originate from mul-
tiple sources including resident fibroblasts (considered the
main source), smooth muscle cells, perivasculature peri-
cytes, epithelial-to-mesechymal and endothelial-to-mesen-
chymal transition, fibrocytes, and other myeloid progeni-
tors. In response to a pathological stress, cardiac fibroblasts
transform to myofibroblasts and express higher levels of

Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org 445

 BERNARDO ET AL.
proinflammatory and profibrotic factors and secrete ECM
proteins to promote wound healing (422). While the initial
transient activation of myofibroblasts is considered an
adaptive response to maintain the structural integrity of the
heart, persistent myofibroblast activation leads to excessive
ECM deposition, and a maladaptive phenotype leading to
the progression of heart failure (422). Factors and signaling
pathways involved in early activation of cardiac fibroblasts
and in pathological remodeling have been the focus of nu-
merous investigations and include angiotensin II, endothe-
lin-1, TGF-␤, RhoA, G protein-coupled receptor kinase 2
(GRK2), Smads, and mitogen-activated protein kinase
(MAPKs) (256, 416, 422, 423). Therapeutic approaches
that target some of these factors have shown some efficacy,
but additional therapies are greatly needed (223, 407).
Since exercise has been shown to have anti-fibrotic proper-
ties in preclinical models of heart disease, this represents an
active area of investigation.
Unlike pathological cardiac hypertrophy, physiological car-
diac hypertrophy in response to moderate aerobic exercise
training is not associated with fibrosis (interstitial or
perivascular) in humans or animal models. In male athletes
(cyclists or weight lifters) with enlarged hearts, there was no
evidence of fibrosis based on imaging techniques (98, 221).
Commonly used exercise training protocols in rodents
(swimming, running) which induce physiological hypertro-
phy are not associated with fibrosis compared with seden-
tary controls (216, 269, 408). For example, it was shown
that collagen content of the cardiac ECM in exercised rats
(10 wk of treadmill running) was not increased, and colla-
gen I/III ratio was maintained (54). Gene expression of
collagen I and III in the hearts of rats was not significantly
changed following a 13-wk treadmill training protocol
(176). No alterations in collagen deposition or osteopon-
tin-1 protein expression were detected in hearts of rats
following 8 wk of treadmill training (289). Furthermore,
expression of ␣-smooth muscle actin, a marker of myo-
fibroblast activation contributing to collagen remodel-
ing, was unchanged in exercise-trained rat hearts after 13
wk of treadmill running (176). However, while fibrosis is
not a feature of the exercise-trained heart, it is notewor-
thy that cardiac hypertrophy in response to exercise or
activation of the IGF1R-PI3K pathway is associated with
changes in the collagen profile (215, 267, 409). The func-
tional significance of these changes is currently not well
understood.
Exercise training has been shown to attenuate fibrosis in
diseased or aging hearts. Swim training in mice was able to
attenuate fibrosis induced by pressure overload or isopro-
terenol (248, 434). Similarly, exercise training (involuntary
treadmill) had no discernible effects on fibrosis and cardiac
remodeling in young rats, but mitigated age-related eleva-
tion of fibrosis in old rats (216, 408). Furthermore, mice
that underwent endurance training for 6 wk before and 4
446 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
wk after anterior MI had a reduction in collagen content in
the left ventricle and also in the scar region (337). Some
studies have identified mechanisms contributing to the anti-
fibrotic effects of exercise, but this represents an area for
further investigation. Fibrosis in the aged rat heart was
associated with an imbalance in the MMP/TIMP ratio (e.g.,
decreased MMPs and increased TIMP-1) and increased
TGF-␤; exercise training attenuated these changes (215,
216). With the use of genetic mouse models, it has been
demonstrated that IGF1, IGF1R, and/or PI3K signaling
protects against cardiac fibrosis in cardiac disease settings
including pressure overload, dilated cardiomyopathy, MI,
and atrial fibrillation (266, 269, 335, 415, 434). Further-
more, approaches that target PI3K-regulated miRNAs also
have been associated with anti-fibrotic properties (see sect.
IVA2B) for further details). AMPK has also been implicated
in the protective effect of swim training against isoprotere-
nol-induced cardiac fibrosis by inhibiting ROS production
(248).
H. Exercise-Induced Inflammatory Response
The effects of exercise on the immune system are complex
and depend on the intensity and duration of the exercise
performed (122). In general, acute or vigorous/high-inten-
sity exercise induces an inflammatory response, character-
ized by an increase in the number of leukocytes in the cir-
culation, a process known as leukocytosis (296, 361), and
increases in circulating cytokines, such as interleukin-6
(IL-6; pro- and anti-inflammatory) and TNF-␣ (pro-inflam-
matory) (48, 122). The demargination and mobilization of
leukocytes during exercise arises from the increase in hemo-
dynamics (which increases shear stress), as well as increased
activation of the sympathetic nervous system (385). The
inflammatory response to acute exercise is transient, return-
ing to baseline within a few days (189). In contrast, regular
physical activity or exercise training is associated with
reduced levels of inflammation. This may provide benefit
in settings of chronic inflammation, such as insulin resis-
tance, obesity, metabolic syndrome, and type 2 diabetes,
conditions that increase cardiovascular disease risk
(113), as well as in aging (131, 345). Exercise training
reduces inflammatory markers in patients with chronic
heart failure (3, 76, 338, 339, 419), a syndrome charac-
terized by low-grade chronic inflammation (99). Whether
the anti-inflammatory effects of exercise directly contrib-
ute to cardioprotection in these settings requires further
investigation.
The molecular mechanisms responsible for the anti-inflam-
matory effects of exercise are still unclear. IL-6 is a cytokine
with both pro- and anti-inflammatory properties (325). In-
creased IL-6 synthesis and secretion from contracting skel-
etal muscle during exercise may provide benefit by promot-
ing the secretion of anti-inflammatory cytokines (such as
IL-10 and IL-1 receptor agonist), reducing TNF-␣ levels
 EXERCISE-INDUCED CARDIAC PROTECTION
and upregulating glucose and lipid metabolism (51, 321).
However, long-term aerobic exercise training reduces basal
IL-6 levels in humans (122) and reduces IL-6 levels in
experimental models of cardiac disease/remodeling. For
example, in a rat model of cardiac hypertrophy induced
by sustained ␤-adrenoceptor stimulation (isoproterenol
administration), treadmill running for 12 wk prevented
isoproterenol-induced increases in myocardial IL-6 and
TNF-␣ expression (375). In an exercise intervention
study, MI caused significant increases in plasma concen-
trations of IL-6 and TNF-␣ in sedentary rats, but not in
rats that underwent 8 wk of treadmill running, 4 wk after
the induction of MI (309). Downregulation of Toll-like
receptor 4 (TLR4) may also contribute to the anti-inflam-
matory effects of exercise. TLR4 is a transmembrane
receptor that induces inflammatory cytokine production
when activated, and TLR4 expression was reduced in
trained subjects compared with sedentary subjects in two
aged cohorts (8 wk/6 mo of resistance training) (263,
350).
Aerobic exercise also indirectly protects the heart via its
effects on the vasculature. During aging, increased oxida-
tive stress and inflammation lead to stiffening of the large
elastic arteries and vascular endothelial dysfunction, which
increases the risk of atherosclerosis and other cardiovascu-
lar diseases. Studies in humans and experimental animals
have demonstrated that aerobic exercise training improves
endothelial function and that the pertinent mechanism in-
volves reduced expression of the pro-inflammatory tran-
scription factor NF-KB and reductions in oxidative stress
(362).
I. Communication Between the Heart and
Other Organs/Systems in Response to
Exercise
Communication between multiple organs/systems in the
body in settings of health and disease has emerged as an
important factor contributing to the final phenotype/pre-
sentation observed in animal models and patients (188,
213, 321). Exercise is recognized to affect numerous sys-
tems within the body, but the underlying mechanisms re-
sponsible for the crosstalk between organs, including con-
tracting organs (heart and skeletal muscle) and noncon-
tracting organs, is not well understood. It has been
proposed that exercise-induced release of factors (e.g., pep-
tides, metabolites, DNA, mRNA, miRNAs, and other RNA
species) from organs may play a role in mediating the mul-
tisystemic effects of exercise. These factors have been
termed “exerkines” and may have effects on distant organs
and cells (i.e., endocrine signaling), in addition to effects on
cells within the same organ (paracrine signaling) or the cell
itself (autocrine signaling). Interest in this research field has
grown with the increased knowledge regarding extracellu-
lar vesicles (exosomes, microvesicles) which contain pro-
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
teins and nucleic acids that can be transported between cells
and tissues (358). There is some evidence to suggest that
exercise can increase the abundance of small extracellular
vesicles in humans (126), and it was reported that exosomes
were released from the hearts of type 2 diabetic (db/db)
mice subjected to acute exercise (64). A recent study dem-
onstrated that an exercise stress test in at-risk human
subjects was associated with an increased quantity of
plasma extracellular vesicles (assessed using nano-flow
cytometry; no significant change in extracellular vesicle
size) (20). The same investigators showed that swim
training in mice for 3 wk was associated with increased
levels of serum extracellular vesicles (~1.85-fold). Injec-
tion of the same quantity of extracellular vesicles from
exercised and sedentary mice into the left ventricle before
ischemia-reperfusion injury provided comparable pro-
tection based on infarct area and markers of apoptosis.
However, injection of exercise-induced extracellular ves-
icles in a quantity similar to that observed with swim
exercise (1.85-fold) significantly reduced infarct area and
apoptosis further (20). Using a cardiomyoblast cell line
(H9C2 cells) in combination with siRNA and chemical
inhibitors, it was mechanistically shown that 1) IGF1 was
sufficient to increase the release of extracellular vesicles
into the cell culture medium, and this was due in part to
increased expression of extracellular vesicle biogenesis-
and secretion-related genes (ALIX and RAB35) in IGF1-
treated cells; and 2) exercise-derived extracellular vesi-
cles protect H9C2 cells from H2O2-induced apoptosis via
ERK1/2 and HSP27. Data from this study suggest that
the exercise-induced increase in the number of extracel-
lular vesicles rather than content mediate cardiac protec-
tion. However, it is noteworthy that there is also evidence
to suggest that exercise can change the contents of extra-
cellular vesicles (64). Additional studies will be required
to identify the major source of exercise-induced extracel-
lular vesicles.
In response to exercise, heart rate increases and blood
flow going to skeletal muscle and the heart increases
significantly. It is recognized that in response to exercise,
contracting skeletal muscle acts as an endocrine organ to
communicate with other tissues/organs such as adipose
tissue, liver, and brain to control energy metabolism
(188, 321). The concept of the heart as an endocrine
organ was recognized in the 1980s with the identification
that ANP and BNP are expressed in the heart and se-
creted upon stimuli such as mechanical and hemody-
namic stress. ANP and BNP control cardiovascular func-
tion via actions on distal tissues including the kidneys,
adrenal, and brain (374). Factors released from the heart
in response to cardiac insults/stress have been identified
(102). To date, factors released specifically from the
heart in response to exercise remain relatively un-
known.
447
 BERNARDO ET AL.

III. GENOME, TRANSCRIPTOME,
PROTEOME, AND METABOLOME:
FROM EXERCISE-INDUCED
SIGNATURES TO THERAPIES AND/OR
BIOMARKERS
The identification of exercise-induced molecular signatures
may hold promise for the development of new therapies or
biomarkers for cardiac pathology and heart failure. Heart
failure was recently classified as the most rapidly growing
cardiovascular condition globally (466). This has been at-
tributed to an increased aging population and preventable
childhood diseases transitioning to cardiovascular diseases.
The majority of cases are considered to be preventable by
targeting lifestyle factors (466). However, this approach is
best implemented by identifying individuals at risk as early
as possible. Regular physical activity is associated with re-
duced incident heart failure (106).
Under basal, exercise, or disease settings, cell functions are
a consequence of complex interactions between networks
of the genome, transcriptome, proteome, and metabolome
(397) (FIGURE 9). Exercise represents a dynamic and com-
plex process. Early studies largely used reductionist meth-
ods/approaches to target individual genes or proteins regu-
lated by exercise. However, significant improvements in
“omics” technologies have substantially enhanced the ca-
pacity to define the relationships between genetics, molec-
ular pathways, and phenotypes. Proteomic and metabolo-
mic measurements have become more reliable with ad-
vances in mass spectrometry. Thus it is now possible to
identify thousands of factors that are regulated in response
to stimuli such as exercise. The current challenge is the
analysis of huge data sets to delineate the key drivers and
complex processes underlying exercise-induced cardiac
protection (119). In this section, we briefly describe some
studies that have explored the effects of exercise on the
cardiac genome, transcriptome, proteome, and metabo-
lome.
A. Genome and Transcriptome
Protein coding genes are the most well-studied sequence,
but only account for ⬍2% of the genome (292). In the
last decade, previously unknown noncoding RNA species
have been discovered and add a new dimension to the
regulation of transcription (292). Here, we highlight
both coding and noncoding RNAs dynamically regulated
in the heart with exercise training (swimming, treadmill
running, voluntary free wheel), as well as genetic-based
rodent models with physiological hypertrophy (e.g.,
transgenic activation of the IGF1-PI3K-Akt pathway)
or artificially selected rats with high running perfor-
mance.

EXERCISE

Genomic
coding DNA PHENOTYPE
GENE ENZYMATIC
TRANSLATION
EXPRESSION FUNCTIONS

GENOME TRANSCRIPTOME PROTEOME METABOLOME

gtcg tacggg g
ccg atgatc
acac ggatcccc tagct
a tg
Next generation Proteins Lipids
ctcgta tcagatac tagcc
ga c c ca a g tt
ccctt ttagga sequencing
tttttaa g P C G A T
Nucleic
Epigenetic acids
factors Gene array Exercise trained
e.g. Methyl group mRNA
Proteins with Amino acids heart
post-translational Sugars
miRNA modifications
e.g. phosphorylation
Genomic Physiological
O-GlcNAc
non-coding cardiac
DNA hypertrophy
Genetic
REGULATORY
variant
RNAs
EXERCISE
miRNA

FIGURE 9. The use of multi-omics platforms to identify novel mechanisms and uncover exercise signatures.
Integrating data from multi-omics systems to understand genetic variants and epigenetic marks (genome and
epigenome), gene expression and miRNAs (transcriptome), proteins (proteome), and metabolites (metabo-
lome) during exercise to define molecular pathways of exercise.

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 EXERCISE-INDUCED CARDIAC PROTECTION
1. Gene expression profiling
In the early-mid 2000s, several groups utilized microarray
technology to investigate gene expression changes in the
hearts of rodents in response to endurance training (swim-
ming and running) (69, 129, 136, 208, 396). These analyses
identified the differential expression of genes involved in
glucose/insulin signaling, protein biosynthesis, epidermal
growth factor signaling, fatty acid oxidation/lipid metabo-
lism and cell survival (69, 129, 136, 208, 396). Galindo et
al. (129) compared 8 different microarray data sets from
models of exercise-induced hypertrophy and identified a set
of 59 genes with functions related to cell growth, heart
contraction, cell death, and ECM organization. Further-
more, the PI3K-Akt signaling pathway was statistically
overrepresented in the identified genes across all models.
These data sets were also compared against rodent models
of pathological hypertrophy and human cardiac disease.
The value of identifying genes differentially regulated in
models of exercise-induced physiological hypertrophy and
models of pathological hypertrophy was highlighted by
Sakamoto et al. (359). Using a DNA chip array, they iden-
tified genes that were upregulated in hearts of rats with
exercise-induced physiological hypertrophy (8 wk of volun-
tary running) but not pressure overload-induced patholog-
ical hypertrophy (5 wk). Approximately 100 genes were
differentially elevated in each model compared with con-
trol. Of these, expression of Hsp70 and HSF1 was higher in
the physiological model but not the pathological model. To
assess the role of HSF1 in the exercise-trained heart, the
investigators subjected HSF1-deficient heterozygote mice
(HSF1⫹/⫺) to voluntary wheel running. The exercise-in-
duced hypertrophic response was not blunted in HSF1⫹/⫺
mice, but cardiac function was impaired, and the typical
exercise-induced increase in Hsp70 was prevented. This re-
sult is consistent with HSF1 and Hsp70 playing a role for
exercise-induced adaptations (see sect. IIF1). Furthermore,
mice with constitutive activation of HSF1 in the heart were
protected in a setting of pressure overload-induced patho-
logical hypertrophy (359).
Gene expression studies have also been undertaken in
hearts from rats artificially selected for high and low run-
ning capacity (HCR and LCR, respectively) (448). By 35
wk, LCR display evidence of cardiac pathological remodel-
ing (myocyte hypertrophy, fibrosis, increased fetal gene ex-
pression) (93, 348) and by 15–20 mo show defects in myo-
cyte function (depressed cardiomyocyte contractile func-
tion and relaxation as well as impaired Ca2⫹ handling)
(165, 204). LCR are also more susceptible to risk factors of
cardiovascular disease (high blood pressure, hyperlipid-
emia, insulin resistance), whereas HCR are protected and
have better myocyte function (448). Between the two
groups, 1,540 of 28,000 screened genes were found to be
differentially expressed. In sedentary LCR, genes involved
in glucose metabolism were more highly expressed in the
heart. In contrast, genes related to lipid metabolism were
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
higher in hearts from sedentary HCR (56). The authors
conclude this suggests a switch from normal fatty acid ox-
idation to carbohydrate metabolism in the LCR. Genes re-
lated to cellular stress (e.g., DNA damage, inflammation)
and pathological growth signaling (e.g., genes associated
with embryonic growth) were also higher in the LCR (56).
Few investigators have conducted profiling studies in large
animal models subjected to exercise. In a swine model that
had undergone treadmill running for 3– 6 wk, the investi-
gators reported that changes in gene expression observed in
rodent models were not necessarily observed in swine.
However, a common feature in the swine and previous ro-
dent studies was the regulation of genes related to PI3K-Akt
signaling (214). In this study, transcription factors differen-
tially regulated between physiological and pathological hy-
pertrophy were also identified including the glucocorticoid
receptor and paired box 6 (Pax6; functional significance in
the heart remains unclear) (214).
More recent studies have used RNA sequencing (RNA-seq)
which allows for higher sensitivity, accuracy, reproducibil-
ity, and the capacity to identify splice variants (253). RNA-
seq performed in hearts of swim-trained mice confirmed
known pathways reported from microarray studies, and
identified novel pathways (e.g., suppression of autoim-
mune-related pathways) and alternative splice variants
(389). Interestingly, the investigators detected more alter-
native splice isoform changes compared with gene expres-
sion changes after exercise, suggesting that exercise-in-
duced cardiac remodeling may be mediated by modification
of critical domains via alternative splicing without quanti-
tative changes in mRNA expression (389). Identified path-
ways related to alternative splicing included cell signaling/
transduction (calcium signaling, insulin signaling) as well as
pathways related to cardiac disease.
To identify key or new regulators of physiological cardiac
hypertrophy and protection, we and others have under-
taken profiling studies in IGF1R, PI3K, and Akt transgenic
mice (236, 267, 370, 384). A large-scale computational
analysis integrating transcriptomic data from in vivo mu-
rine models of physiological cardiac hypertrophy (short-
term cardiac-specific Akt transgenic induction, cardiac ac-
tivation of PI3K:caPI3K transgenic, swimming) identified a
conserved core network involved in processes such as coor-
dinated regulation of angiogenesis, induction of autophagy
compatible with cell survival, the TSC2/mTOR pathway,
and mitochondrial cytochrome c oxidase (last component
to the electron transport chain that facilitates the aerobic
production of ATP) (103). In another profiling study we
compared gene expression in hearts from caPI3K mice
with physiological hypertrophy (due to increased PI3K),
hearts from dnPI3K mice (with smaller hearts due to
decreased PI3K), and hearts from a cardiac disease model
(MI) (236). Using bioinformatics we filtered for genes
449
 BERNARDO ET AL.

that were differentially regulated in the different models,
correlated with heart function, and selected genes with
relatively high expression in the heart. Growth factor
receptor-bound 14 (Grb14) represented one of the top
candidate genes, but the role in the heart was largely
unknown. We subsequently studied Grb14 KO mice and
showed that Grb14 protects the heart against cardiac
pathology under basal conditions and in a setting of MI.
Loss of Grb14 in mice induced a pathological cardiomy-
opathy characterized by an increase in heart and atrial
weight, depressed cardiac function, interstitial fibrosis,
and decreased activation of Akt (236). This strategy
highlights the potential of identifying novel downstream
functional targets that may be manipulated/targeted as
therapeutic approaches.
2. Noncoding RNAs
Noncoding RNAs include miRNAs, PIWI-interacting
RNAs, small nucleolar RNAs, and long noncoding RNAs
(292). To date, the best studied noncoding RNAs are miR-
NAs. miRNAs are small noncoding RNAs (~19 –24 bp) that
have been shown to regulate gene/protein expression (26).
miRNAs can be regulated by exercise, as well as by signal-
ing cascades in the heart which induce exercise-induced
physiological heart growth (e.g., PI3K).
A) EXERCISE-REGULATED miRNAs. miRNAs dynamically regulated
after swimming or running in rodents and mouse models of
physiological hypertrophy have been reviewed in detail in
References 315 and 117. Three cardiac specific miRNAs
(miR-1, miR-133a, miR-133b) were the first miRNAs to be
studied in exercise models. Two separate groups confirmed
downregulation of these miRNAs in swim-trained and
interval-trained rats (61, 388). However, these miRNAs
were also decreased in a model of pathological hypertro-
phy induced by pressure overload (61). Subsequently, a
number of groups have tried to identify miRNAs that
play distinct roles in the heart in a setting of exercise and
disease.

miR-134 miR-21 miR-206

miR-1
miR-208a miR-146a miR-208b
miR-222
miR-133a miR-20a
miR-126 miR--221
Circulation
miR-499 EXERCISE miR-149*

Cardiac tissue: myocyte, fibroblast etc. miR-99b miR-222

miR-29a,c miR-100 miR-126
miR-17
miR-143 miR-144
miR-154 miR-124
miR-21 ↓ p27
↑ IGF1R miR-19b
miR-27a,b ↓ HIPK1
↓ TIMP3 ↓ Spred-1
↑ ACE2 ↑ p15 miR-223
↑ PI3K ↓ PTEN
↓ Collagen miR-34 ↓ PI3KR2
genes miR-145 (p85β)
↓ ACE miR-208a/b
↑ Ang (1-7) ↑ Akt
↓ TSC2 miR-652 Cell cycle/
↓ Ang II proliferation ↑ MAPK
↑ αMHC
miR-26b
miR-27a
↓ GSK3β ↓ βMHC
↑ Jagged1 ↑ PI3K-
↑ Vinculin ↑ Vegf Akt-
miR-214 eNOS
Anti-fibrotic
↓ Pathological actions
remodeling Physiological
↑ Serca2a
heart growth & Anti-apoptotic
cell survival Preservation of
cardiac contraction & Angiogenesis
electrical conduction

FIGURE 10. miRNAs regulated by exercise or PI3K in the heart and circulation. An overview of cardiac and
circulating miRNAs regulated by exercise or PI3K and changes in their target genes (direct/indirect) that may
contribute to characteristic features associated with physiological cardiac hypertrophy. miRNAs that are
downregulated are highlighted in green, and miRNAs upregulated are highlighted in blue. miR-17 in this figure
is the miR-17-3p strand.

450 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org

 EXERCISE-INDUCED CARDIAC PROTECTION
Several groups have discovered miRNA signatures in hearts
of exercise rodent models (swim training and strength train-
ing in rats) which target genes associated with collagen
deposition/fibrosis (miR-29) (388), angiogenesis (miR-126)
(84), the renin-angiotensin system (miR-143, miR-27a,
miR-27b) (118), the PI3K/Akt/mTOR pathway (miR-21,
miR-144, miR-124, miR-145, miR-19b, miR-99b, miR-
100) (249), Akt/GSK3␤ (miR-26b, miR-27a) (257),
SERCA2a (miR-214) (272), and ␣/␤ MHC ratio (miR-
208a/b by targeting Med13, Pur␤, Sox6, Sp3, HP1␤) (387)
(FIGURE 10).
miRNAs are also regulated in rodent hearts in response to
exercise in a heart disease setting (273, 274, 393). Three
miRNAs (miR-1, miR-29, and miR-24) were dysregulated
in a setting of MI, and exercise training prevented this dys-
regulation, at least in part (273, 274). Another group iden-
tified a set of miRNAs (miR-598, miR-429, miR-224, miR-
425, miR-221) that were regulated by treadmill exercise in
a rat model of heart failure due to aortic stenosis. It was
suggested that regulation of these miRNAs may provide
protection because they target genes related to cell death,
TGF-␤ signaling, and metabolic processes (393).
To date, the functional significance of the majority of exer-
cise-regulated miRNAs in directly mediating exercise-in-
duced remodeling and protection has not been comprehen-
sively assessed in vivo. Examples of miRNAs that have been
examined and shown to have a biological role are miRNA-
222, miR-223, and miR-17–3p. miR-222 was robustly up-
regulated in hearts of mice in response to exercise (volun-
tary wheel-running or swim training), and miR-222 was
shown to target cell proliferative genes (243). Inhibition of
miR-222 prevented the increase in exercise-induced heart
growth; however, transgenic cardiac overexpression of
miR-222 was not sufficient to induce an increase in heart
size with exercise training (243). miR-223 was also found to
be elevated in hearts of treadmill trained mice, and cardiac
overexpression of miR-223 induced physiological heart
growth (enhanced cardiac function, no fibrosis) (457). The
key direct targets of miR-223 responsible for inducing phys-
iological heart growth are not entirely clear as miR-223 was
shown to regulate both pro-hypertrophic and anti-hyper-
trophic signaling pathways. The investigators postulate
that the pro-hypertrophic pathways outweigh the anti-hy-
pertrophic pathways, and this leads to secondary Akt acti-
vation and physiological hypertrophy (457). A recent study
demonstrated that the expression of miR-17 (miR-17–3p)
was upregulated in hearts from mice after voluntary wheel
running for 21 days and in isolated adult cardiomyocytes
from mice that had undergone swim training for 21 days
(380). Conversely, the expression of miR-17 was decreased
in cardiac tissue under pathological settings (a mouse model
of pressure overload induced by transverse aortic constric-
tion and in human dilated cardiomyopathy heart samples)
(380). Further supporting the role of this miRNA in exer-
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
cise, serum levels of miR-17 were increased in chronic heart
failure patients following an exercise test. Inhibition of
miR-17 with an antagomiR in mice partially blocked exer-
cise-induced heart growth in vivo. This was associated with
attenuation of myocyte hypertrophy, reduced markers of
cardiomyocyte proliferation, and regulation of TIMP3,
PTEN, and Akt signaling (380).
B) EXERCISE-INDUCED CIRCULATING miRNAs.The expression of
miRNAs also change in the circulation in response to
exercise (FIGURE 10). The exact source of these miRNAs
is unclear, but they have the potential to act on the heart
and other organs. Circulating miRNAs (c-miRNAs) are
protected from degradation through inclusion in extra-
cellular vesicles or association with RNA-binding protein
complexes (80). The regulation of c-miRNAs in response
to different modes of exercise (marathon running, row-
ing, resistance training) have recently been reviewed
(330) and are considered to have potential value as exercise
biomarkers and markers of fitness capacity.
Baggish et al. (15) reported a unique signature set of
c-miRNAs that were dynamically regulated in response to
acute exhaustive cycling exercise and sustained aerobic
rowing exercise training in healthy competitive athletes
(miR-21, miR-146a, miR-221, and miR-222; miR-20a was
upregulated only in response to sustained exercise training).
However, this study only investigated c-miRNAs with
known roles related to exercise adaptations such as angio-
genesis, exercise-induced inflammation, and skeletal and
cardiac muscle contractility. Since this study, Sawada et al.
(364) performed microarray analysis of c-miRNAs and
their response to acute resistance training. Circulating levels
of miR-149/miR-149-3p were increased following resis-
tance training, whereas miR-146a and miR-221 were sig-
nificantly reduced post resistance training. Investigation
of heart/muscle specific miRNAs (myomiRs) and inflam-
mation-related miRNAs in plasma of male endurance
athletes following a marathon run revealed increased ex-
pression levels of the myomiRs miR-1, miR-133a, miR-
206, miR-208b, and miR-499, whereas the fibrosis/in-
flammation-related miRNAs (miR-21 and miR-155)
were not affected by exercise (288). Similarly, another
study identified a robust increase in circulating levels of
miR-1, miR-133a, miR-208a, and c-miR-146a in athletes
immediately following prolonged aerobic exercise (i.e., a
marathon run); miR-134, miR-126, and miR-499 were also
altered but to a smaller degree. miR-1 and miR-208a were
not affected after acute exhaustive exercise (upright cycling
of 30 min duration). Thus the duration and type of exercise
appears to affect the regulation of muscle specific c-
miRNAs (16).
C) PI3K-REGULATED miRNAs. Using the same approach utilized to
identify Grb14 (see sect. IIIA1), we identified a set of 62
miRNAs (e.g., miR-34, miR-652, miR-154) differentially
451
 BERNARDO ET AL.
regulated in caPI3K and dnPI3K hearts and diseased hearts
due to MI (236). These miRNAs have mRNA targets that
can regulate angiogenesis, cardiac contraction, electrical
conduction, apoptosis, and fibrosis (FIGURE 10). PI3K-reg-
ulated miRNAs (miR-34, miR-652, and miR-154) and an
exercise-regulated miRNA (miR-222) have subsequently
been targeted in cardiac disease settings and shown to pro-
vide benefit (see sect. IVA2B).
3. Genetic variants
Whole genome sequencing (WGS) provides the most com-
prehensive coverage of an individual’s genetic variation.
WGS allows for sequencing of the entire genome including
1) protein coding genes, 2) noncoding intronic regions of
genes, and 3) large tracts of intergenic sequences. With a
substantial reduction in DNA sequencing costs over the last
decade (cost per genome in 2006 ⬎$10M vs. 2015–2016
~$1K) (296a), and improvements in technology and bioin-
formatics, WGS has become a realistic alternative to tar-
geted panel screens (e.g., 50 –100 cardiac disease-related
genes) and exome sequencing (captures 1% of the genome
that codes for proteins). Over 150 genetic markers have
been linked to athletic performance (6). It will be important
to confirm these genetic variants in larger cohorts. How-
ever, it is of interest that some of the variants have been
identified in genes involved in processes associated with
exercise-induced cardiac adaptation including cardiac
growth (IGF1R), angiogenesis (NOS3/eNOS, VEGF),
and E-C coupling (KCNJ11, encodes Kir6.2). With fu-
ture studies utilizing WGS, the discovery of additional
genetic variants is anticipated. In combination with in
silico modeling, this may provide important insight on
gene variants associated with differential responses to
exercise (adaptive/maladaptive and/or responders/nonre-
sponders) (6).
B. Epigenetic Adaptations
Epigenetics (histone acetylation, histone methylation, and
DNA methylation) has emerged as a major mechanism reg-
ulating gene expression. One well-known histone modifica-
tion is histone acetylation, tightly regulated by two families
of enzymes known as histone acetyltransferases (HATs)
and histone deacetylases (HDACs). Enzymes involved in
histone acetylation have been extensively studied in patho-
logical cardiac remodeling; class I HDACs (HDAC 1,2,3)
promote transcription of hypertrophic genes, while class IIa
HDACs (HDAC 4,5) repress hypertrophy (433). Another
widely studied epigenetic mark is DNA methylation. A hy-
permethylated DNA region is strongly correlated with gene
suppression.
Exercise-induced epigenetic adaptations in the heart have
not been examined extensively. A single bout of acute ex-
ercise did not alter the protein levels of HDACs 1–5 and
452 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
components of the HDAC complex in mice (271), but an-
other study showed increased cardiac HDAC2 activity fol-
lowing 3 days of forced swimming (194). Findings with
chronic exercise training have also been variable. While one
study reported no significant change in the activity of
HDAC enzymes in the hearts of mice that underwent
chronic exercise (voluntary wheel running for 3 wk; trend
for an increase in class IIa and b in males) (209), another
study in high-volume swim-trained rats (10 wk) reported
increased protein expression of HDAC1 and decreased
HDAC3 and HDAC4 protein levels (387).
Several studies have documented exercise-induced epige-
netic changes in endocrine tissues/cells (fat, blood, brain,
skeletal muscle) that may directly or indirectly exert down-
stream effects on the heart (reviewed in detail in Refs. 96,
237, 308, 467). In human adipose tissue biopsies, individ-
uals involved in a 6-mo moderate-intensity exercise pro-
gram displayed hypermethylation of genes (including
HDAC4) with parallel changes in gene expression (352).
After a single bout of exercise, skeletal muscle biopsies from
normal individuals demonstrated changes in genome-wide
histone acetylation and DNA methylation levels (264). The
authors showed augmented nucleo-cytoplasmic shuttling of
HDAC4 and elevated ubiquination levels of HDAC5
through exercise (264). Furthermore, disruption of class IIa
HDAC corepressor complexes with the HDAC inhibitor
Scriptaid recapitulated the effects of exercise in mice, in-
creasing the expression of metabolic genes in skeletal mus-
cle when administered acutely, and enhancing whole-body
energy expenditure, increasing lipid oxidation, and reduc-
ing fasting blood glucose levels when administered chroni-
cally (130).
Translocation of class IIa HDACs (e.g., HDAC4 and
HDAC5) from the nucleus to the cytosol promotes cardio-
myocyte hypertrophy in vitro (153, 287, 426) and has been
documented in the failing myocardium (164). However, the
effects of exercise on the subcellular localization and func-
tion of cardiac class IIa HDACs require further investiga-
tion. An elegant study by Backs et al. (13) demonstrated
that acute ␤-adrenergic activation (as occurs during ex-
ercise) leads to PKA-dependent proteolytic cleavage of
HDAC4 and accumulation of the resulting NH2-terminal
fragment (termed HDAC4-NT) in the nucleus.
HDAC4-NT contains a myocyte enhancer factor-2
(MEF2) binding domain and selectively represses MEF2
activity, preventing the transcription of genes involved in
pathological remodeling; the activity of other transcrip-
tion factors, such as SRF (which is associated with cell
survival) was unaffected. It has been proposed that this
mechanism protects the heart from undergoing maladap-
tive remodeling in physiological stress settings (such as
during exercise, which leads to repetitive transient eleva-
tions in catecholamines).
 EXERCISE-INDUCED CARDIAC PROTECTION
C. Proteome
Significant developments in the field of proteomics includ-
ing sample preparation and enrichment strategies, high-res-
olution mass spectrometers, and high-throughput analysis
tools have allowed investigators to study proteins in much
greater depth, including the identification and role of pro-
tein posttranslational modifications (PTMs) (120, 401).
PTMs including phosphorylation, N-glycosylation,
O-GlyNAcylation, proteolytic cleavage, redox, deamida-
tion, sumoylation, citrullination, methylation, and lysine
acetylation have been identified within numerous compart-
ments/organelles within cardiac myocytes including the cell
membrane, cytoplasm, mitochondria, SR, Golgi apparatus,
nucleus proteasome, and sarcomere (234, 401). Conse-
quently, PTMs have the potential to affect numerous pro-
cesses within the heart including E-C coupling, metabolism,
gene transcription, and cell survival/death. Data are emerg-
ing to show that acute and/or chronic exercise can regulate
total protein expression and PTMs in the rodent heart from
healthy animals and models of disease. Ferreira et al. (119)
integrated cardiac proteomics data from eight studies in
which rats had been subjected to exercise training (swim-
ming or treadmill) for different time periods (2, 6, 8, or 54
wk). Some common proteomic signatures included upregu-
lation of antioxidant systems, activation of kinases (e.g.,
PKA), fatty acid oxidation, vasculogenesis, and tissue re-
generation (119). One study identified changes in the phos-
phorylation profile of mitochondrial proteins that was in-
dicative of increased glucose oxidation, protein translation,
and redox protection (120). Exercise (acute or chronic) has
also been associated with decreased cardiac protein O-
GlcNAc by a number of groups (22, 24, 271); an exception
to this was in a mouse model of type 2 diabetes, in which
moderate treadmill exercise increased protein O-GlcNAc in
the heart (79). Increased levels of O-GlcNAc are a feature of
many pathologies including diabetes, aging, ischemia, and
heart failure. However, whether this increase contributes to
declining heart function or is an adaptive mechanism in
response to stress, is unclear (255). The therapeutic poten-
tial of targeting proteins that play roles in mediating exer-
cise-induced physiological hypertrophy is highlighted by
the identification of Hsp20. Hsp20 was detected by mass
spectrometry and two-dimensional electrophoresis exclu-
sively in hearts from exercise-trained rats (6 wk of progres-
sive treadmill running) (42, 55), and cardiac-specific trans-
genic overexpression of Hsp20 was able to protect the heart
against cardiac injury (115).
D. Metabolome
Metabolomics or metabolite profiling refers to the system-
atic analysis of metabolites within a biological sample (e.g.,
blood, urine, biological tissues). Metabolites are defined as
low molecular weight biochemicals and include nucleo-
tides, sugars, amino acids, organic acids, and lipids (346,
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
376). Since metabolites are downstream of transcriptional,
translational, and posttranslational processes, they are con-
sidered to serve as the most proximal readouts of changed
conditions (e.g., exercise or disease) (FIGURE 9). Conse-
quently, metabolomics may have potential for identifying
novel biomarkers with clinical utility, as well as mecha-
nisms of cardiovascular disease development and exercise-
induced protection (376), particularly in individuals who
are well phenotyped and serve as their own biological con-
trols (346). Another potential advantage of profiling the
metabolome is the more manageable number of metabolites
(estimated ⬍10,000) in comparison to the genome
(⬎20,000 genes), transcriptome (⬎106 mRNAs), and pro-
teome (⬎106 proteins). Mass spectrometry and nuclear
magnetic resonance spectroscopy have been the two main
technologies used for metabolite profiling.
Metabolomics has already shown its utility as a tool in
humans for assessing the effect of exercise on cardiac risk
markers such as insulin resistance (376). Exercise inter-
ventions (low-, moderate-, and high-intensity exercise:
cycle ergometer, treadmill, elliptical trainers) in seden-
tary, overweight, or mildly obese subjects (STRRIDE
trial) were associated with alterations in metabolic pro-
files. These profiles were indicative of more efficient mi-
tochondrial fatty acid oxidation and were associated
with reduced cardiac risk markers (e.g., improved insulin
sensitivity) (166, 376). It was also shown that metabolic
signatures obtained during exercise (treadmill or cycle
ergometer) in human subjects with normal exercise ca-
pacity (no evidence of myocardial ischemia) provided
signatures of exercise performance and susceptibility to
cardiovascular disease (230). Changes in metabolites re-
flected alterations in glycolysis, lipolysis, adenine nucle-
otide catabolism, amino acid catabolism, glycogenolysis,
oxidative stress, and insulin sensitivity. Furthermore, a
set of metabolites that were identified in humans during
exercise were able to regulate the expression of transcrip-
tional regulators of metabolism in cell culture (cultured
myotubes), and one was confirmed in skeletal muscle of
mice (230).
Metabolic signatures in response to exercise have also
been identified in animal studies. Monleon et al. (286)
performed metabolic profiling on plasma from mice sub-
jected to 18 mo of spontaneous exercise (running wheels
provided to mice at 3 mo of age). Voluntary exercise for
18 mo was accompanied by increased maximal running
capacity and grip strength. Alterations in plasma metab-
olites in the exercise group (at rest) were indicative/sug-
gestive of increased lipolysis (increased total fatty acids,
unsaturated fatty acids, glycerol), altered glucose metab-
olism (decreased alanine and lactate), altered catechol-
amine synthesis (elevated tyrosine and phenylalanine),
and increased phospholipid metabolism (lower choline).
Heart glucose consumption (assessed by positron emis-
453
 BERNARDO ET AL.

sion tomography) was also lower in the exercise group, IV. THERAPEUTIC STRATEGIES:
possibly due to increased fatty oxidation in the heart TARGETING THE PROTECTIVE ACTIONS
(although not confirmed in this study) (286). OF EXERCISE

Lai et al. (220) performed metabolic profiling and transcrip-
tomic profiling in hearts from mice with compensated hy-
pertrophy due to pressure overload (TAC) and decompen-
sated hypertrophy (TAC together with a small MI), and
compared this to hearts from mice with physiological hy-
pertrophy (8 wk of voluntary wheel running; less cardiac
enlargement than the pathological models). The metabolo-
mics signatures were shown to more robustly distinguish
the exercise and pathological models than the transcrip-
tomic results. In the decompensated heart failure model, the
metabolite profile (e.g., increased acylcarnitine species) sug-
gested a bottleneck in carbon substrate flux (fatty acids and
glucose) into the TCA cycle which could limit ATP produc-
tion and cause contractile dysfunction. In contrast, many of
these metabolites were decreased in the exercise-trained
heart, suggesting matched carbon substrate flux and no
bottlenecking.
Earlier sections of this review highlight the wide range of effects
that exercise has on a number of cell types, organelles, and pro-
cesses within the heart, as well as other systems/organs that can
then have secondary effects on the heart. It is unlikely a single
therapeutic intervention would meet the criteria of recapitulating
all the beneficial effects of exercise. However, a number of ap-
proaches that target key mechanisms responsible for exercise-
induced remodeling have been targeted and shown some degree
of protection (FIGURE 11).
A. Approaches Targeting the IGF1-PI3K-Akt
Pathway
The IGF1-PI3K(p110␣) pathway is elevated in the heart
in response to exercise in animal models and humans
(refer to sect. IIB1; Refs. 33, 35, 435), and numerous
groups have demonstrated that various IGF1, IGF1R,

EXERCISE
NATURAL PRODUCTS
Flavonoids NH2 OH

O N
Icaritin N

Benfotiamine N SMALL
MOLECULE
Ca2+ ISCHEMIC IGF1
BGP-15
CONDITIONING
ICaL IGF1R

Cytoplasm

Ca2+ RNAi BASED THERAPIES &

OLIGONUCLEOTIDES miR-222
PI3K-regulated miR-17-92
PI3K
miRNAs cluster
Sarcoplasmic antimiR-34a/34
RyR2
reticulum
antimiR-652
Ca2+ SMALL
antimiR-154 MOLECULE
SERCA2a GENE THERAPY
X SC79
2+
Ca Akt
SUMO1 AAV-caPI3K
SUMO1

SMALL
Regulation of
MOLECULE
miRNA targets Proliferation of
N106
GENE THERAPY cardiac myocytes
AAV-SERCA2a

Reduced pathology
Improved/preserved heart function
FIGURE 11. Therapeutic strategies: targeting the protective actions of exercise. A schematic representing
gene-based (RNAi and viral vectors), natural products, ischemic conditioning, or small molecule-based thera-
pies that target the IGF1R-PI3K-Akt signaling axis or calcium handling.

454 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org

 EXERCISE-INDUCED CARDIAC PROTECTION
PI3K(p110␣), and Akt genetic mouse models are pro-
tected in models of cardiac stress/disease including pres-
sure overload (266), dilated cardiomyopathy (266, 415,
437), diabetic cardiomyopathy (181, 349), atrial fibrilla-
tion (335), and models of oxidative stress and ischemia
(e.g., MI) (233, 236, 428). IGF1 and/or PI3K have also
been shown to regulate a number of processes/responses
that are also mediated by exercise including cardiac myo-
cyte growth, angiogenesis, electrical remodeling, and E-C
coupling; attenuation of fibrosis; promotion of cell sur-
vival; and regulation of mitochondrial function. Thus
enhancing cardiac IGF1-PI3K(p110␣) signaling in pa-
tients with heart failure may be beneficial. However, in
the majority of studies using the IGF1/IGF1R/PI3K/Akt
genetic mouse models, gene expression had been modi-
fied before a cardiac insult/stress or simultaneously with
the stress. For an approach to enter the clinic, it is neces-
sary to assess interventions at clinically relevant time
points to develop and identify tools or agents with the
potential to enter the clinic (i.e., interventions that can be
administered and provide benefit once cardiac pathology
is present). Acute versus chronic activation of a pathway
or target also needs to be considered. Even though the
majority of IGF1/IGF1R/PI3K/Akt transgenic models
have shown protection in cardiac stress settings (265),
there are also examples where this approach has not had
a favorable outcome. For instance, long-term transgenic
expression of the IGF1 ligand in the heart transitioned
from a physiological to pathological cardiac hypertro-
phic phenotype in mice (92). In addition, clinical trials in
which IGF1 was chronically administered to humans
were disappointing (73, 344). One explanation for neg-
ative or adverse findings could be related to chronic IGF1
elevation activating fibroblasts and causing cardiac fibro-
sis. Over time, this would lead to pathological hypertro-
phy and cardiac dysfunction. Subsequent clinical trials
used recombinant human growth hormone (rHGH) to
increase circulating IGF1 levels. Preliminary studies re-
ported favorable effects of rHGH administration on clin-
ical symptoms and heart function (116, 132, 262). How-
ever, improvements in heart function were not recapitu-
lated in a large-scale clinical trial (317), possibly due to
acquired growth hormone resistance, a syndrome that
affects 60 –70% of cachectic heart failure patients (10).
For long-term treatments, cardiac selectivity or specific-
ity is also of importance given that uncontrolled activa-
tion of the IGF1-PI3K-Akt pathway can cause tumori-
genesis in other organs and cell types (95, 127, 174).
Thus investigators have explored and developed new
strategies for activating the IGF1-PI3K-Akt pathway in
the heart. These include different delivery systems, at-
tempts to target damaged heart tissue, small molecules,
ischemic conditioning (pre-, post-, and remote-condi-
tioning), and naturally occurring compounds, such as
herbs (FIGURE 11 AND TABLE 3).
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
1. Strategies targeting IGF1/IGF1R
A) IGF1. Investigators have explored whether intrapericardial
delivery of IGF1 or targeting IGF1 to injured heart tissue is
able to mediate protection without adverse consequences.
Some preliminary data show favorable outcomes. How-
ever, animal numbers have been low or follow-up periods
have been short (TABLE 3). Thus further studies are
warranted.
B) IGF1R: BGP-15, SMALL MOLECULE WHICH INCREASES IGF1R PHOSPHORY-
LATION. BGP-15 is a hydroximic acid derivative that was
known to act as a co-inducer of the stress-inducible form of
Hsp70 in some cell types (81), but whether it would induce
Hsp70 in the adult stressed heart in vivo was unknown. We
previously found that Hsp70 was elevated in the exercise-
trained heart and caPI3K transgenic mouse heart, but not in
the dnPI3K exercise-trained heart which showed a blunted
physiological hypertrophic response (434). In addition,
Hsp70 was known to provide benefit in acute cardiac stress
settings (34). BGP-15 had also been tested in clinical trials
for other diseases (e.g., diabetes) and shown to be safe and
well tolerated, with no cardiac side effects being reported
(239). Thus it was of interest to examine whether BGP-15
provided any therapeutic benefit in mouse models with car-
diac pathology. Oral administration of BGP-15 in mice
with heart failure and atrial fibrillation for 4 wk was asso-
ciated with reduced episodes of arrhythmia, improved car-
diac function, and decreased cardiac fibrosis (363). How-
ever, unexpectedly, the mechanism by which BGP-15 ex-
erted its protective effects appeared to be via increased
phosphorylation of the IGF1R, rather than via the induc-
tion of Hsp70 expression (363). BGP-15 provided benefit in
a heart failure model in which Hsp70 had been deleted, and
BGP-15 was shown to phosphorylate the IGF1R in neona-
tal rat ventricular myocytes (363). Daily administration of
BGP-15 is considered to cause a short pulsatile increase in
IGF1R signaling because BGP-15 has a relatively short half-
life (81). Thus this may reduce the potential for chronic
long-term adverse effects observed with chronic IGF1 li-
gand delivery.
2. Strategies targeting PI3K
We developed an adeno-associated viral
A) PI3K GENE THERAPY.
(AAV) vector encoding the same caPI3K(p110␣) construct
to that used to generate the caPI3K transgenic mice (434).
Recombinant AAV serotype 6 (rAAV6) was combined with
the cytomegalovirus (CMV) promoter to achieve robust
and selective expression in cardiac myocytes (140, 434).
Adult mice administered rAAV6-CMV-caPI3K developed
physiological hypertrophy, reminiscent to that of exercised
trained mice and caPI3K transgenic mice (434). Next, we
investigated the therapeutic potential of rAAV6-CMV-
caPI3K administration in mice with established LV remod-
eling and cardiac dysfunction (4 wk of pressure overload
induced by TAC) (434). Mice administered rAAV6-CMV-
455

Table 3. Interventions associated with protection and activation of the IGF1-PI3K-Akt pathway
Intervention/Drug
IGF1 conjugated to Hoechst (histological
stain that binds to double-stranded
DNA); tail vein injection
Intrapericardial delivery of IGF1 (150
␮g·kg-1·day-1) for 14 days
BGP-15
AAV6-caPI3K
PI3K-regulated miRNAs: miR-34 family
PI3K-regulated miRNAs: miR-34a
PI3K-regulated miRNAs: miR-652
456 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
BERNARDO ET AL.
Cardiac Stress Model
Myocardial IR in mice
MI in sheep (occlusion of LAD
with gel foam; procedure
repeated until ejection
fraction was ⱕ40%)
Mice with heart failure and
atrial fibrillation
Pressure overload in mice
Study 1: pressure overload
(transverse aortic
constriction, TAC) in mice
Study 2: MI in mice
Study 1: pressure overload in
mice
Study 2: dilated
cardiomyopathy (DCM)
Study 3: heart failure and
atrial fibrillation
Pressure overload in mice
Reference
Observation Nos.
Intravenous delivery of Hoechst-IGF1 (H-IGF1) 199
selectively bound to exposed DNA and
targeted the injured heart. Twenty-eight
days post-MI, H-IGF1 was associated with
preserved cardiac function and less
fibrosis.
IGF1 was associated with increased ejection 261
fraction which remained elevated 14 days
after the last treatment (compared with
control saline); Note: only 3 sheep in each
group.
Administration of BGP-15 by oral gavage was 363
associated with reduced episodes of
arrhythmia, improved cardiac function, and
decreased cardiac fibrosis.
Improved cardiac function, increased 434
angiogenesis, and more favorable
expression of proteins involved in
cardiomyocyte contraction.
Study 1: treatment with antimiR-34 28
improved cardiac function and attenuated
lung congestion. This was associated with
reduced cardiac fibrosis, increased
angiogenesis, increased Akt activity,
decreased atrial natriuretic peptide gene
expression, and maintenance of
sarcoplasmic reticulum Ca2⫹-ATPase gene
expression.
Study 2: treatment with antimiR-34
attenuated cardiac remodeling and atrial
enlargement in the MI model.
In both studies, improved outcome in
antimiR-34-treated MI and TAC mice was
accompanied by upregulation of several
direct miR-34 targets, including vascular
endothelial growth factors, vinculin, protein
O-fucosyltranferase 1, Notch1, and
semaphorin 4B.
Study 1: inhibition of miR-34a in mice with 27, 32
moderate cardiac pathology attenuated
atrial enlargement and maintained cardiac
function, but had no significant effect on
fetal gene expression or cardiac fibrosis.
Inhibition of miR-34a in mice with severe
pathology provided no therapeutic benefit.
Study 2: disease prevention in LNA-antimiR-
34a-treated DCM female mice was
characterized by attenuated heart
enlargement and lung congestion, lower
expression of cardiac stress genes (B-type
natriuretic peptide, collagen gene
expression), less cardiac fibrosis, and
better cardiac function
Study 3: no evidence of significant protection
in the severe heart failure and atrial
fibrillation model in either sex.
Inhibition of miR-652 improved cardiac 31
function, attenuated cardiac hypertrophy,
reduced cardiac fibrosis, was associated
with less apoptosis, and preserved
angiogenesis. Jagged1 (a miR-652 target
and Notch1 ligand) protein and mRNA was
upregulated with antimiR-652 treatment.
Continued
 EXERCISE-INDUCED CARDIAC PROTECTION

Table 3.—Continued
Reference
Intervention/Drug Cardiac Stress Model Observation Nos.

PI3K-regulated miRNAs: miR-154
Akt gene therapy
SC79-Akt activator
Flavanol extraction from propolis
(traditional medicine)
Icaritin (traditional Chinese medicinal
herb)
Benfotiamine (Vitamin B1 analog which
directs glucose to the pentose
phosphate pathway)
Sevoflurane (inhaled anesthetic)-induced
postconditioning (SPC)
Ischemic preconditioning (IP)
Pressure overload in mice
Ischemia-reperfusion injury in
rodents
Ischemia (35 min) and
reperfusion (60 min) in
rats
Isoproterenol-induced cardiac
hypertrophy in mice (25
mg·kg-1·day-1 for 7 days)
Myocardial IR in rats
Study 1: type 1 diabetes
model (STZ) and type 2
(db/db)
Study 2: type 1 diabetic mice
(STZ) subjected to MI
Myocardial IR in rats
MI in pigs (LAD ligation,
measured 7 days post-MI)
Treatment with antimiR-154 improved 30
cardiac function and attenuated
pathological remodeling. Treatment was
associated with attenuation of heart and
cardiomyocyte size, less cardiac fibrosis,
lower expression of ANP and BNP,
attenuation of profibrotic markers, and
increased expression of p15 (a miR-154
target and cell cycle inhibitor).
Decreased apoptosis and/or infarct size and 128, 260
improved cardiac function.
No protection against ischemic injury and no 290
reduction in infarct size.
Flavanol attenuated isoproterenol-induced 400
increases in ANP and ␤-MHC. The flavanol-
induced response was prevented with
wortmannin* (PI3K inhibitor). No cardiac
function measures with isoproterenol,
flavanol and with or without wortmannin.
Icaritin reduced infarct size and was 464
associated with increased Akt
phosphorylation, reduced markers of
inflammation and oxidative stress, and
better cardiac function. Wortmannin
inhibited some measures of icaritin-
induced protection (infarct size, markers of
inflammation, and oxidation).
Study 1: benfotiamine prevented systolic and 191
diastolic dysfunction in vivo, and treatment
was associated with increased Akt
signaling. Some beneficial responses of
benfotiamine in cardiac myocytes (e.g., cell
survival) were attributed to PI3K-Akt
signaling by using LY294002 and Ad.DN-
Akt. However, the contribution of the PI3K-
Akt pathway in vivo was not assessed.
Study 2: benfotiamine treatment 190
administered 4 wk before MI was
associated with better post-MI survival and
cardiac function as well as less apoptosis.
In vitro studies in cardiac myocytes with
Ad.DN-Akt implicated Akt signaling.
SPC protects against IR injury (infarct size, 462
cardiac dysfunction, apoptosis). BEZ235
(PI3K/mTOR dual inhibitor) blunted SPC-
induced protection (infarct size, contractile
dysfunction, apoptosis).
IP was associated with smaller infarct size, 398
fewer malignant ventricular arrhythmias,
less collagen content, better systolic
function, and vascular density.
LY294002* (PI3K inhibitor) prevented the
IP-induced protection.

*Wortmannin and LY294002 can regulate targets other than PI3K. DCM, dilated cardiomyopathy; IP, ischemic preconditioning; IR, ischemia-
reperfusion; LAD, left anterior descending artery; MI, myocardial infaraction; STZ, streptozotocin; TAC, transverse aortic constriction.

caPI3K displayed improvements in systolic function over
the 10 wk following rAAV6-CMV-caPI3K delivery. At the
end of the study period, fractional shortening of treated
mice had returned to pre-surgery values, whereas systolic
function of control mice remained poor (434). Improve-
ments in heart function were accompanied by increased
angiogenesis and more favorable expression of proteins in-
volved in cardiomyocyte contraction (MHC isoforms and
SERCA2a). This study provides evidence that increasing
cardiac PI3K(p110␣) activity after the onset of cardiac dys-

Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org 457

 BERNARDO ET AL.
function can improve outcome (434). The same PI3K gene
therapy also provided protection in a mouse model of dia-
betic cardiomyopathy with established diastolic dysfunc-
tion (334). With advances in vector technology, design, and
delivery, gene therapy represents a promising therapeutic
strategy for the treatment of cardiac disease (146).
B) PI3K-miRNA BASED DRUGS.Studies in our laboratory identified
miRNAs regulated by PI3K(p110␣) activity that were also
dysregulated in a cardiac disease setting (MI) (236). Manip-
ulation of miRNA expression (using miRNA inhibitors) has
shown favorable therapeutic outcomes in patients with hep-
atitis C virus (169) and is also being explored as a therapeu-
tic approach for cancer (14). With optimization of cardiac
delivery systems, this approach may also represent a feasi-
ble avenue for the successful development of a miRNA-
based therapy for the treatment of heart failure. Inhibition
of candidate PI3K-regulated miRNAs (miR-34, miR-34a,
miR-652, or miR-154) using miRNA inhibitors was associ-
ated with reduced pathology and better cardiac function in
mouse models of MI and/or pressure overload. Improved
outcomes were accompanied by the upregulation of target
genes implicated in regulating cardiac contractility, preserv-
ing angiogenesis and cell survival, and inhibiting fibrosis
and inflammatory responses (27, 28, 30 –32) (FIGURE 10).
Additional reports have shown that miR-34a is also ele-
vated in the aged heart and other models of ischemia and
that inhibition of miR-34a provides benefit via additional
target genes associated with protection against DNA dam-
age and telomere shortening as well as myocyte prolifera-
tion and regeneration (43, 458). When inhibiting specific
disease-regulated miRNAs, it is important to consider the
potential regulation of additional miRNAs. Inhibition of
miR-34 was shown to target secondary miRNAs (miR-31,
let-7e) via transcription factor-miRNA regulatory net-
works, i.e., some miRNAs can regulate the expression of
transcription factors that regulate the expression of other
miRNAs (316).
3. Strategies targeting Akt
A) AKT GENE THERAPY. Akt1 is required for exercise-induced
physiological cardiac hypertrophy in mice (91) and is rec-
ognized to play a central role in mediating cardioprotection
(155). Thus several groups have investigated the effects of
Akt gene therapy in the adult rodent heart. Akt adenoviral
gene transfer in the rat heart increased the contractility of
isolated hearts (10 days post-delivery before significant car-
diac growth), most likely due to more systolic Ca2⫹ avail-
ability (71). In addition, Akt gene therapy was also protec-
tive in rodent models of ischemia. Akt gene therapy admin-
istered to mice 20 h before ischemia-reperfusion injury
protected myocytes from apoptosis (128), and in vivo gene
transfer of Akt in a rat model of cardiac ischemia-reperfu-
sion decreased the number of apoptotic cardiac myocytes
and infarct size and improved cardiac function (260).
458 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
B) AKT SMALL MOLECULE: SC79-AKT ACTIVATOR. Pharmacological ac-
tivation of Akt has also been considered an approach that
may be useful in promoting myocyte survival in the diseased
heart. The small molecule SC79 was shown to activate Akt
in the adult rat heart (290). However, acute pharmacolog-
ical activation of Akt by SC79 failed to reduce infarct size
and did not protect the rat heart against ischemic injury
(290). Further studies examining dose and timing of admin-
istration may be warranted.
4. Naturally occurring compounds acting via the
PI3K-Akt pathway
A number of naturally occurring compounds have been
shown to possess cardioprotective properties, and many of
these are reported to act, at least in part, via activation
of the PI3K-Akt pathway. The interpretation of a number of
these studies has been based on experiments using the PI3K
inhibitors wortmannin or LY294002. Some caution needs
to be taken when considering the conclusions of these re-
ports because both inhibitors have the potential to inhibit/
interact with other lipid kinases and proteins (17, 134).
Naturally occurring compounds considered to act via PI3K-
Akt signaling (e.g., flavonoids, icaritin, benfotiamine) are
summarized in TABLE 3.
5. Ischemic conditioning and protection via
PI3K-Akt signaling
Ischemic conditioning (pre-, post-, remote-) has provided
some degree of protection in preclinical settings, and one of
the key mechanisms implicated is PI3K-Akt signaling.
However, activation of PI3K-Akt may occur downstream
of receptors other than IGF1R; mechanisms involving
eNOS and S6K1 have also been implicated. However, de-
spite positive results in rodent models, findings in the clinic
have been quite variable (154). There is also some evidence
that limb ischemic preconditioning may enhance athletic
performance, though further studies are required and the
mechanisms are unclear (379).
6. Exercise-regulated miRNAs with proliferative
capacity
Exercise training in mice has been shown to stimulate car-
diomyocyte proliferation (44). The injured adult heart has a
limited capacity to regenerate, and the loss of cardiomyo-
cytes in the adult heart is a key component of most heart
failure pathologies. Thus therapeutics that can promote
cardiomyocyte proliferation may have a beneficial effect on
cardiac repair and regeneration. A number of miRNAs have
been reported to promote cardiomyocyte proliferation in
the mouse heart, and some appear to be regulated in the
heart or circulation by exercise including miR-222 and
members of the miR-17–92 cluster (15, 243, 341, 380).
The expression of miR-222 was shown to be increased in
the hearts of mice subjected to voluntary wheel running or
 EXERCISE-INDUCED CARDIAC PROTECTION
swim training (243). In addition, in humans miR-222 in-
creased in the plasma of athletes after both acute and
chronic exercise (15), and in heart failure patients following
cardiopulmonary exercise testing (243). Targets of miR-
222 including p27 and HIPK1 were shown to contribute to
the pro-proliferative effects of miR-222. While miR-222
was shown to be required for exercise-induced cardiac
growth, and transgenic overexpression of miR-222 pro-
tected the heart against cardiac dysfunction after ischemic
injury, an approach to pharmacologically increase miR-222
is yet to be described (243).
Two members of the miR-17–92 cluster (miR-19b and
miR-20a) were shown to be elevated with exercise. miR-
19b expression was elevated in the hearts from rats sub-
jected to swim training for 8 wk based on small RNA se-
quencing (similar trend by qPCR) (341). Circulating levels
of miR-20a were increased in healthy competitive athletes
after 90 days of sustained aerobic rowing exercise (15).
Cardiac-specific overexpression of the miR-17–92 cluster in
mice induced cardiomyocyte proliferation in embryonic,
neonatal, and adult mouse hearts (66). Furthermore, over-
expression of this cluster protected the mouse heart from
MI-induced injury through increased cardiomyocyte prolif-
eration, decreased infarct size, and improved cardiac func-
tion (FIGURE 11) (66). Another member of the miR-17–92
cluster, miR-17–3p, which contributes to exercise-induced
cardiac growth and regulates markers of myocyte prolifer-
ation, was also shown to have protective properties. In a
setting of ischemia-reperfusion injury, mice treated with a
miR-17–3p agomiR (which increased miR-17–3p expres-
sion ~6-fold) displayed preserved cardiac function, attenu-
ation of cardiac apoptosis and fibrosis, and increased mark-
ers of cardiomycoyte proliferation (380).
Collectively, these studies suggest that targeting miRNAs
that are regulated in settings of protection (i.e., mimicking
exercise) represents a promising approach for the develop-
ment of a novel miRNA-based therapy for the failing heart.
B. Therapies Targeting Calcium Handling
As described in section IID1B, exercise is known to have
beneficial effects on calcium handling in the heart by in-
creasing SERCA2a uptake/activity/protein (195, 197, 198,
447). For example, exercise training in rats was shown to
improve contractility, increase calcium sensitivity, and nor-
malize SERCA2a protein levels after MI (446). Investiga-
tors have developed therapies that target SERCA2a directly
or target regulators/modifiers of SERCA2a such as small
ubiquitin-like modifier-1 (SUMO1) (FIGURE 11). Preclinical
studies in small and large heart failure animal models have
demonstrated improvement in cardiac function and remod-
eling as a consequence of overexpression of SERCA2a using
adenoviral vectors (57, 193, 281). Following these success-
ful preclinical studies, clinical trials were conducted and
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
SERCA2a was delivered to the myocardium of patients
with heart failure using an AAV vector approach. Results
from phase 1 and 2 clinical trials of AAV-mediated gene
transfer of SERCA2a in patients with heart failure demon-
strated clinical benefits in patients receiving AAV-
SERCA2a (improvements in LV function/remodeling and 6
min walking time) (170, 173, 470). However, results from a
larger international clinical trial with AAV-SERCA2a in
patients with moderate-severe heart failure were not asso-
ciated with any benefits (139). Potential reasons for the
negative findings were identified as suboptimal vector dose,
reduced transduction efficiency, and delivery method (139,
342). However, despite the disappointing results from the
recent trial, the impetus for continuing to pursue gene ther-
apy for heart failure remains strong (342). A number of
research groups and companies worldwide are designing
second- or third-generation AAV vectors (e.g., chemical
modifications such as PEGylation to make AAVs immuno-
logically inert), as well as investigating other delivery sys-
tems (280, 342). Furthermore, promising results were iden-
tified in a small phase 2 clinical trial in heart failure patients
with intracoronary gene transfer of adenylyl cyclase 6
(AC6; acts via regulating cAMP and SERCA2a). Improve-
ments were observed in ejection fraction at 4 wk post-de-
livery, and there was a decline in heart failure symptoms by
12 wk (150).
SERCA2a activity has also been targeted by the modifica-
tion of SUMO1 (required for preserving SERCA2a function
by SUMOylation) by either viral vector gene transfer (200,
413) or administration of a novel small molecule, N106
(FIGURE 11) (201). Both approaches were able to improve
cardiac function and increase SUMOlyation of SERCA2a in
animal models of heart failure.
C. Gene Therapy Approaches Targeting the
Protective Actions of Exercise:
Challenges and Potential for Turning
Experimental Laboratory Findings Into
Clinical Therapeutics
A significant attraction of using gene therapy for the heart
to mimic the protective actions of exercise (e.g., by targeting
PI3K-Akt signaling or calcium handling as described above)
is the potential to more specifically or selectively target the
heart. However, although many preclinical studies have
shown benefit of gene transfer in animal models of heart
failure, clinical trials have generally failed to meet primary
efficacy end points (70, 139, 150). A key contributing factor
is the difficulty of transducing the human heart efficiently
(147). Despite this, the recent favorable safety profile of
gene delivery vectors targeting the heart in patients allows
further progress in this field (324). Hajjar and Ishikawa
(147) have recently outlined three approaches to improve
cardiac gene delivery. One option is to increase gene dose of
the vector; however, patients would have to be monitored
459
 BERNARDO ET AL.
closely for an increased immune response and arrhythmias.
A second strategy being actively pursued is to develop a
more efficient gene delivery method. However, this is usu-
ally associated with a more invasive method of delivery
(e.g., retrograde coronary sinus delivery). Thus this ap-
proach may be better suited to patients requiring a surgical
procedure, such as a valve replacement. Finally, the third
approach is to use vectors in the clinic with a higher trans-
duction efficacy (e.g., AAV9), or a reengineered vector with
higher cardiac tropism. Both of these strategies have been
used successfully in preclinical large animal models (168,
329). It is expected that some of these approaches will be
incorporated into upcoming clinical trials (147).
V. OBSTACLES AND CHALLENGES
A. Comprehensively Capturing the
Mechanisms Responsible for Exercise-
Induced Cardiac Protection
Defining the full complement of molecular and cellular
changes (acute and chronic) associated with exercise is chal-
lenging given exercise represents a dynamic stimulus affect-
ing numerous organs and systems in the body; during the
exercise bout but also during the recovery phase. It is also
unclear whether mechanisms identified in the most com-
mon exercise training models in animals (i.e., moderate
swim, treadmill, and voluntary free wheel protocols) reflect
mechanisms that may occur with other common forms of
exercise in humans (e.g., cycling, weight training). With
“lack of time” being a common reason provided for not
undertaking regular exercise (418), there has been increased
interest and research into assessing the potential benefits of
intermittent bursts of relatively intense exercise [e.g., high-
intensity training, sprint interval training (SIT)] (135). SIT
was associated with improved measures of cardiometabolic
health (e.g., peak oxygen uptake and insulin sensitivity)
despite the lower exercise volume and reduced exercise time
(135). Furthermore, positive short-term effects of interrupt-
ing prolonged periods of sitting with light-intensity physical
activity (e.g., standing, stepping) on cardiometabolic health
have been reported (111, 157). To date, the effects of acute
versus chronic and low/moderate- versus high-intensity ex-
ercise on the cellular and molecular mechanisms in the heart
have not been studied in detail.
B. Few Drugs Translating From the
Research Laboratory to the Clinic
For most human diseases, the number of drugs being suc-
cessfully translated to the clinic has been disappointing, and
lower than anticipated in the last decade. There are many
reasons that have been attributed to this failure including
lack of reproducibility of basic science studies (e.g., lack of
rigor, nonspecific antibodies), species differences, effects of
460 Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
anesthesia, more strict regulatory requirements, an in-
creased aversion to risk from pharmaceutical companies,
increasing clinical trial costs, inappropriate patient popula-
tions selected (including sex differences), and unexpected
toxic effects (77, 207, 425, 432). An additional challenge
facing the cardiovascular research community was recently
highlighted, i.e., inadequate assessment of cardiovascular
functional measurements as laboratories with physiology
expertise dwindle in favor of molecular-based laboratories
(425).
Preclinical studies in which key regulators of exercise-in-
duced protection have been targeted have been promising.
However, innovative strategies for specifically targeting the
heart or diseased myocardium may be required. Future
studies in large-animal models and clinical trials will be
required to assess how these approaches compare with cur-
rent drugs prescribed as standard of care. In considering the
multitude of effects exercise has on numerous cell types and
processes within the heart and other organs, the discovery
of a single target or “exercise pill” with the ability to reca-
pitulate all the salutary effects of exercise is probably un-
likely. Given exercise represents an effective nonpharmaco-
logical approach, the strategy of treating patients so they
are able to undertake some form of exercise, and subse-
quently prescribe pharmacological agents together with ex-
ercise is worthy of further study in animal studies and hu-
mans. The combination of a ␤-blocker together with exer-
cise training in heart failure mice provided benefits above
either intervention alone based on measures including sur-
vival, exercise tolerance, and cardiac contractility (424).
However, in prescribing exercise as a therapeutic interven-
tion, it is also important to consider the physical and psy-
chological road blocks that deter people from undertaking
exercise on a regular basis. This is particularly challenging
for the aged. It remains unknown why some individuals
enjoy exercise and for others it is a chore. Further research
should be undertaken to understand the effects of exercise
on the brain and behavioral patterns.
1. Species differences: mouse versus human
Genetic mouse models have proven a valuable tool for un-
derstanding the mechanisms underlying exercise-induced
cardiac protection. However, there are key similarities and
differences between species that must be considered when
assessing the potential of translating a finding from mice to
humans. Mice and humans have a genome size that is sim-
ilar (mice: 2,600 Mb, human: 3,000 Mb), a comparable
number of genes (~30, 000 in both), and many proteins
show conserved function (229, 319). The mouse and hu-
man heart are both four-chambered organs, and electrical
signals are propagated in a similar way. However, there are
also key differences including the heart size, heart rate, vas-
culature, and differences in the contribution of some con-
tractile proteins (e.g., ␤-MHC predominates in the human
 EXERCISE-INDUCED CARDIAC PROTECTION
heart and ␣-MHC predominates in the mouse heart; sex
difference is also apparent) (40, 229).
2. Sex differences in settings of cardiac health
and disease
Cardiovascular research in both humans and animals has
been carried out predominately in males (1, 186, 228); how-
ever, it is now well recognized that there are distinct differ-
ences between the male and female heart (23, 343). Sex
differences have been identified in cardiac size, cardiac func-
tion, E-C coupling (AP, myocyte contraction), cardiac gene
expression, energy metabolism (glucose uptake, fatty acid
utilization), and the activation of signaling pathways (40,
89, 138, 303, 417). This is particularly true in settings of
cardiac disease, and males and females respond differently
to cardiovascular drugs (35, 186, 245, 333). There is also
increasing evidence to show exercise-induced cardiac re-
modeling differs in males and females in animals and hu-
mans, although larger studies with more power will be re-
quired in humans (343). Early studies performed in rats
demonstrated that female rats displayed a greater cardiac
hypertrophic response (increased heart/body weight ratio
of 31%) compared with male rats (increased heart/body
weight ratio of 17%) following 8 wk of swim training (5
days/wk) (366, 367). In another study, treadmill running (5
days/wk for 8 wk) resulted in increased cardiac hypertrophy
in both male and female rats, but only isolated hearts from
trained male rats showed enhanced cardiac performance
(365). In mice, females developed more cardiac hypertro-
phy in response to voluntary running and treadmill running
compared with males (87, 105, 124, 209, 210), but this
difference was eliminated when mice were placed on a ca-
sein-based soy-free diet (209). In addition, female mice ex-
hibited enhanced wheel running performance (running fur-
ther and for longer; independent of strain and age) (105,
210), and female mice performed better than male mice in
endurance and stress treadmill tests (209).
The underlying mechanisms responsible for the sex-medi-
ated differences in exercise-induced cardiac remodeling are
not well understood, but contributing factors include sex
hormones and the interaction of these hormones with mul-
tiple signaling pathways (e.g., IGF1-PI3K-Akt), metabo-
lism, and miRNAs (40, 411). The effect of estrogen in the
sexually dimorphic cardiac response to exercise has been
investigated in genetic mouse models with chronic deletion
of all estrogens [aromatase (Ar) KO mice which produce no
estrogens], and in mice lacking estrogen receptor ␣ (ER␣
KO) or ER␤ (ER␤ KO). Following voluntary wheel running
(7 days and 21 days), Ar KO female mice ran significantly
less than wild-type females but developed equivalent car-
diac hypertrophy, suggesting that estrogens influence run-
ning distance but not cardiac growth in response to exercise
(145). No differences were observed between male Ar KO
and wild-type mice (145). Studies in ER KO models have
been varied and complicated in global KOs in which run-
Physiol Rev • VOL 98 • JANUARY 2018 • www.prv.org
ning behavior is different (105, 311). Following 8 wk of
exercise-induced physiological hypertrophy (voluntary
wheel running), female ER␣ KO mice ran less and did not
develop cardiac hypertrophy compared with wild-type lit-
termates, whereas ER␣ KO male mice performed similar to
their wild-type littermates (105). In contrast, neither male
nor female ER␤ KO mice developed cardiac hypertrophy
compared with sedentary controls, despite similar running
behavior (measured by distance ran) compared with wild-
type littermates. The authors concluded that exercise-in-
duced cardiac hypertrophy depends on ER␤ in both sexes
(105). It is thought that ER␤ mediates exercise-induced car-
diac hypertrophy in female mice by modulating Akt and
MAPK phosphorylation, but the underlying mechanism re-
mains to be elucidated in male mice (105).
A number of signaling mechanisms associated with exer-
cise-induced cardiac protection are likely to be different in
males and females. The IGF1-PI3K-Akt pathway that plays
a key role for exercise-induced hypertrophy and protection
has been shown to be higher in cardiac tissue from females
compared with males (40, 60). Other studies have identified
alterations in signaling in female and male hearts in re-
sponse to exercise including Akt, Hsp70, CaMK, p38-
MAPK, ERK1, and S6 phosphorylation (105, 210, 277,
320, 410). On the basis of animal and human studies, car-
diac substrate availability and utilization also seem to differ
in males and females in response to exercise. However, data
are currently limited, and findings are quite variable. This is
particularly true in human studies, potentially explained by
differences in age and the type and duration of exercise
activity performed (chronic/acute, aerobic/anaerobic) (124,
162, 303, 323, 326, 392, 394, 399, 440). Collectively, these
differences have implications for therapeutic approaches.
For instance, since components of the IGF1-PI3K-Akt path-
way are enhanced in the heart from females (40, 60), ap-
proaches that target this pathway are likely to have differ-
ential therapeutic effects between sexes. As an example, we
recently demonstrated that a miRNA-based therapy that
targeted a PI3K-regulated miRNA (miRNA-34a) had dis-
tinct effects on global miRNA expression in male and fe-
male hearts, and this was associated with more efficacy in
the female disease model (dilated cardiomyopathy) than the
male model (32).
VI. PERSPECTIVES AND CONCLUSIONS
Exercise has well-recognized beneficial effects on the heart
in settings of health and disease and represents one of the
few interventions known to reverse cardiac remodeling and
improve heart function in heart failure patients. This has led
to intense interest in identifying the key mechanisms re-
sponsible for exercise-induced cardiac protection. Studies
examining the effects of perturbing individual genes glob-
ally or specifically in cardiac myocytes in mouse models
have provided significant insight into understanding the
461
 BERNARDO ET AL.
critical molecular mechanisms responsible for exercise-in-
duced cardiac hypertrophy. However, our understanding of
the effects of exercise and genes regulated by exercise on cell
types other than myocytes, organelles, and processes [e.g.,
E-C coupling, mitochondrial adaptations, cellular stress re-
sponses (ER stress response, autophagy, proteasome-ubiq-
uitin system, DNA damage response), and extracellular ma-
trix] is relatively limited. Research within these understud-
ied areas, together with the ability to profile the genome,
transcriptome, proteome, and metabolome in far greater
depth than ever before, opens up new opportunities to more
comprehensively define the signaling and regulatory aspects
of cell/organelle functions that underpin the protective
properties of exercise. An increased knowledge of exercise-
induced changes to the circulation will also be essential for
understanding how the heart interacts with others organs
and systems in response to exercise. Collectively, this has
the potential to lead to the discovery of new drug targets for
heart disease.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: J. Mc-
Mullen, Baker Heart and Diabetes Institute, PO Box 6492, Mel-
bourne 3004, Australia (e-mail: julie.mcmullen@baker.edu.au).
GRANTS
J. R. McMullen is a National Health and Medical Research
Council Senior Research Fellow (1078985). B. C. Bernardo
is supported by an Alice Baker and Eleanor Shaw Fellow-
ship (Baker Foundation, Melbourne, Australia), and K. L.
Weeks is supported by a National Heart Foundation of
Australia Postdoctoral Fellowship (O12M6802).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
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