Reviews

Exercise adaptations: molecular

mechanisms and potential targets
for therapeutic benefit
Sean L. McGee   1 ✉ and Mark Hargreaves2 ✉
Abstract | Exercise is fundamental for good health, whereas physical inactivity underpins
many chronic diseases of modern society. It is well appreciated that regular exercise improves
metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations
observed in skeletal muscle are partly mediated by transcriptional responses that occur
following each individual bout of exercise. This adaptive response increases oxidative capacity
and influences the function of myokines and extracellular vesicles that signal to other tissues.
Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal
muscle gene expression response to exercise as well as of their upstream signalling pathways
has advanced substantially in the past 10 years. With this knowledge also comes the opportunity
to design new therapeutic strategies based on the biology of exercise for a variety of chronic
conditions where regular exercise might be a challenge. This Review provides an overview
of the beneficial adaptive responses to exercise and details the molecular mechanisms involved.
The possibility of designing therapeutic interventions based on these molecular mechanisms is
addressed, using relevant examples that have exploited this approach.

1
Metabolic Research Unit,
School of Medicine
and Institute for Mental and
Physical Health and Clinical
Translation (iMPACT), Deakin
University, Geelong, Victoria,
Australia.
2
Department of Physiology,
The University of Melbourne,
Parkville, Victoria, Australia.
✉e-​mail: sean.mcgee@
deakin.edu.au;
m.hargreaves@
unimelb.edu.au
https://doi.org/10.1038/
s41574-020-0377-1
Chronic diseases associated with inactivity and/or
overnutrition are becoming increasingly prevalent in
modern society. Exercise is known to have numerous
posi­tive health benefits and is efficacious in the pri-
mary prevention of 35 chronic diseases, including
type 2 diabetes mellitus, non-​alcoholic fatty liver disease,
cardio­vascular disease and certain cancers1. Regular
exercise results in a number of adaptive responses that
contribute to its positive health benefits2. Although many
of these adaptations are observed primarily in skeletal
muscle, exercise also has positive effects in other tissues3.
For various reasons, not all individuals are able to
meet the levels of exercise required to experience the
wide-​ranging health benefits that exercise confers.
Consequently, considerable interest has been shown by
researchers in mimicking these effects with pharma-
ceuticals. However, as exercise imparts such complex
perturbations to homeostasis depending on its mode,
intensity and duration, it would be naive to envisage that
the health benefits of exercise in their entirety could be
mimicked with drugs. Nonetheless, knowledge of the
biology of exercise could potentially be harnessed to
improve therapeutic approaches to combat chronic
diseases. Indeed, engaging only a fraction of the adap-
tive response to exercise might still confer important
health benefits. Our understanding of the molecular
mechanisms involved suggests that repeated, transient
increases in the expression of exercise-​responsive genes
in skeletal muscle confer exercise adaptations over
time and contribute to the positive effects of exercise2,4.
Therefore, understanding the molecular mechanisms
mediating this response might reveal new therapeutic
targets for the design of novel medicines to improve the
treatment of a wide range of chronic conditions.
This Review provides a conceptual overview of
exercise adaptations, how they impart a wide range
of health benefits and the hierarchy of the molecular
mechanisms involved. In addition, we highlight proof-
of-​concept examples where an understanding of the
bio­logy of exercise has revealed molecular targets that
have been therapeutically exploited to deliver important
health benefits.
Skeletal muscle adaption to exercise
Skeletal muscle is a key tissue for human locomotion
and, by virtue of its mass and metabolic capacity, it also
has a major role in determining whole-​body functional
capacity, exercise performance and health outcomes.
The contraction of skeletal muscle during exercise
increases force production and energy demand, with
concomitant activation of intramuscular metabolic
pathways responsible for ATP generation as well as

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Reviews
Key points
• Exercise is effective in the primary prevention of 35 chronic diseases.
• The adaptive response to exercise, which is mediated in part by transcriptional
alterations in metabolic and other genes, is an important contributor to these health
benefits.
• Identifying the mechanisms that mediate the exercise adaptive response could
uncover molecular targets to guide the design of new medicines to better treat
chronic diseases.
• A number of signalling, epigenetic and transcriptional molecules identified as
contributing to the exercise adaptive response have been targeted pharmacologically
to deliver health benefits in proof-​of-​concept studies.
• A further understanding of the complexities of the molecular responses to exercise
will provide new opportunities to engage these mechanisms therapeutically.
for the various physiological systems responsible for
oxygen and substrate supply, carbon dioxide removal,
heat removal, fluid balance and overall homeostatic
regulation5. Repeated bouts of exercise as part of a
training programme induce long-​lasting adaptations,
which are dependent on the maintenance of an ongoing
exercise stimulus.
Exercise modality. In exercise physiology, the classic
distinction has been between training characterized by
low load, high repetition (endurance, for example, long
duration cycling) and high load, low repetition (strength
or resistance, for example, heavy weight lifting) exercise
bouts6,7. These are two extremes on a continuum of
muscle contractile activation, and training programmes
often incorporate both at various times8. Since the early
2000s, a resurgence of interest has occurred in high
intensity interval training to induce cardiovascular and
metabolic adaptations9.
The primary adaptations to endurance training are
increased cardiorespiratory fitness, as demonstrated
by increased maximal oxygen uptake and increased
muscle oxidative capacity. This change is facilitated by
mitochondrial biogenesis and angiogenesis, with little,
if any, change in muscle mass. Despite it not increasing
muscle mass, endurance exercise can be effective in
delaying and even preventing age-​related loss of muscle
mass10. By contrast, strength training results in increased
muscle fibre diameter and muscle mass; however, some
effects can be exerted on metabolic capacity. For example,
endurance exercise results in increased mitochondrial
protein synthesis with no change in myofibrillar pro-
tein synthesis, whereas resistance exercise is associated
with an increase in both myofibrillar and mitochondrial
protein synthesis in untrained individuals11. This effect
might be partly related to the metabolic perturbations
that occur in both types of exercise, especially in the
untrained state.
Mechanisms of skeletal muscle exercise adaptation.
The traditional parameters of exercise training pro-
grammes, such as load or intensity, duration and fre-
quency, have multiple and diverse effects on the various
intra­muscular and hormonal signals that potentially
mediate skeletal muscle adaptations. These signals
include but are not limited to increased catecholamine
signalling, sarcoplasmic calcium release, alterations in
496 | September 2020 | volume 16 www.nature.com/nrendo
mechanical force and stretch, metabolic perturbations,
disruptions to the acid–base balance and redox state,
elevated muscle temperature and increased circulating
concentrations of adrenaline5. These upstream signals
can act by engaging transmembrane receptors and acti-
vating downstream signalling pathways, as is the case for
hormonal signals such as catecholamines. Alternatively,
exercise-​associated signals can directly activate exercise-​
responsive signalling molecules, such as AMP-​activated
protein kinase (AMPK), to propagate the exercise signal.
Exercise induces alterations in cellular energy bal-
ance that can result in exercise intensity-​dependent
activation of AMPK in skeletal muscle12. Once acti-
vated, AMPK signals to downstream substrates (for
example, acetyl-​CoA carboxylase and the TBC1 domain
family member 4) that aim to restore energy balance13.
Similarly, the calcium–calmodulin dependent protein
kinase II (CaMKII) is directly activated by increased
cytoplasmic calcium levels, such as those that occur dur-
ing muscle contraction14. Indeed, this kinase is activated
by exercise in skeletal muscle15 and has been implicated
in various exercise responses, including gene expression
responses16 and glucose uptake17. It is important to note
that exercise provides pulsatile and transient signals that
result in physiological adaptations, as opposed to persis-
tent signals that are often associated with pathological
adaptations. For example, an increase in the levels of the
catecholamines adrenaline and noradrenaline during
exercise has an important role in regulating substrate
metabolism and cardiovascular responses to exercise18.
Catecholamines quickly return to pre-​exercise levels
15–60 min after exercise, depending on its intensity
and duration19. However, persistently elevated levels of
catecholamines are associated with pathological cardiac
hypertrophy, hypertension and other chronic health
conditions20. Similar transient signalling in response to
exercise is observed in skeletal muscle. The activity of
AMPK in skeletal muscle returns to pre-​exercise levels
3 h after the completion of exercise21, and chronic AMPK
activity is associated with pathological adaptations such
as cardiomyopathy22,23.
The main research focus on endurance training adap-
tations has been on the importance of calcium dynamics,
metabolic perturbations, and reactive oxygen species
production and their signalling via various kinases
(for example, CaMKII and AMPK) to the molecular
processes involved in mitochondrial biogenesis6,7,24. By
contrast, the research focus for resistance training has
been on the various stimuli for muscle hypertrophy that
signal via the mechanistic target of rapamycin complex 1
(mTORC1) pathway3,4. These signalling pathways are
not independent and complex; indeed, convergent and
divergent interactions probably occur depending on the
nature of the muscle contractile stimuli8. As an example,
the skeletal muscle expression of the glucose trans-
porter GLUT4 is increased in response to endurance25,
sprint interval26 and resistance27 training. Currently,
it is unclear whether this effect reflects multiple signals
converging on a common signalling network, a com-
mon signal targeting multiple signalling pathways, or
some combination of both. As is often the case in bio­
logy, there are multiple, complex and redundant control

systems that regulate homeostatic responses to stressors
such as exercise.
Studies of AMPK loss-​of-​function animal models
have highlighted the complexity of exercise adaptive
responses. For example, mice with deletion of a key
catalytic AMPK subunit or mice that overexpress a
kinase-​dead version of this subunit both show normal
metabolic and adaptive responses to exercise 28–30.
In these AMPK-​defective mice, exercise activates protein
kinase D, which has a similar substrate specificity to
AMPK but is not activated by exercise in wild-​type
mice31; this finding emphasizes that redundant systems
control important physiological responses such as
during exercise. Furthermore, studies utilizing phospho­
proteomics have observed that the phosphorylation of
many phosphosites was altered by various exercise
regimes32–34, which raises the possibility that numerous
other exercise-​regulated kinases and substrates are
important in the response to exercise.
In light of the key role that muscle oxidative capacity
has in determining muscle metabolism, exercise
capacity and health35–37, the molecular mechanisms
responsible for the exercise-​induced increase in muscle
oxidative capacity are the focus of the current Review.
The regulation of muscle mass and exercise-​induced
muscle hypertrophy are reviewed elsewhere38,39.
Effects of exercise on other tissues
Although much attention has focused on skeletal muscle
adaptations to exercise, all organ systems of the body are
affected by both acute bouts of exercise and long-​term
exercise programmes5,40 (Fig. 1a). The improved cardiac
and vascular function with exercise training contri­
butes to increased aerobic capacity and the protective
effects of exercise on cardiovascular disease risk40. The
increased oxidative capacity specifically in the heart has
an important role in this response41. In skeletal muscle,
endurance training leads to substantial effects on
energy metabolism35,36 as well as to effects in the liver42
and adipose tissue43,44. For example, oxidative capacity
is an independent predictor of the abundance of liver
fat in humans45, which is important as the prevalence of
non-​alcoholic fatty liver disease is increasing in parallel
with that of obesity46. Furthermore, endurance exercise
training reduces human liver fat even in the absence
of weight loss, which is thought to be driven by mito-
chondrial biogenesis in hepatocytes that increases their
capacity to oxidize lipids47.
Exercise training in rodents also increases mito­
chondrial biogenesis and the oxidative capacity of white
adipose tissue48, whereas it is unclear whether these same
metabolic alterations occur in response to exercise in
brown adipose tissue 43. In mice, these adaptations
in white adipose tissue are associated with a beiging
phenotype, where white adipose tissue assumes some of
the characteristics of brown adipose tissue, that increases
fatty acid utilization and is thought to prevent the accu-
mulation of ectopic lipid in other peripheral tissues43.
However, a number of studies have found that exercise
training in humans had no effect on markers of oxidative
capacity or beiging of subcutaneous adipose tissue49–52.
Whether adipose beiging and increased oxidative
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capacity in adipose tissue is a rodent-​specific pheno­
menon remains to be determined53 and could explain the
discordance between rodent and human studies43,48–52.
Cognitive function and brain health are also influ-
enced by exercise in humans, and this is particularly
rele­vant to healthy ageing54. Emerging evidence also
suggests that exercise influences the gut microbiome,
which has emerged as a major modulator of metabolism
in health and disease55.
The role of exercise-​induced endocrine factors. Contr­
acting skeletal muscle is well known to release meta­
bolites such as lactate, glycerol and alanine, which have
a key role in intermediary metabolism during exercise.
Over the past two decades, researchers have shown con-
siderable interest in other bioactive molecules released
from contracting skeletal muscle, the so-​called myo­
kines. The interest in myokines was initially catalysed by
observations related to exercise and muscle-​derived IL-6
(ref.56). Numerous cytokines, peptides and meta­bolites
are now recognized to be released from contracting
skeletal muscle during exercise57,58. These various fac-
tors could mediate many of the systemic benefits of
exercise, for example, via effects on adipose tissue, liver57,
pancreas59, heart, blood vessels40 and brain60.
An interesting question relates to the extent to
which muscle oxidative capacity might influence the
production and release of myokines before and after
exercise training. Of note, the release of bioactive mole­
cules during exercise is not limited to skeletal muscle.
Exercise-​induced adaptations in adipose tissue influ-
ence whole-​body glucose and lipid metabolism and
insulin action. In 2019, TGFβ2 was identified as an
exercise-​induced adipokine in mice that is sensitive
to lactate produced by contracting skeletal muscle61.
Furthermore, TGFβ2 appeared to confer some of the
beneficial effects of exercise training in glucose toler-
ance61. Similarly, alterations in the circulating levels
of leptin seem to mediate exercise-​induced effects on
haematopoietic progenitor cells and leukocyte pro-
duction as well as an exercise-​associated reduction in
cardiovascular inflammation in mice62. In addition,
numerous exercise-​induced hepatokines exist in both
mice and humans that could mediate the beneficial
effects of exercise on metabolism, insulin action and
inflammation63. Finally, faecal microbiota transplanta-
tion from human marathon runners to mice improved
exercise performance in the mice64, leading to the idea
that short-​chain fatty acids produced by gut microbiota
might mediate some of the benefits of exercise in various
organs55,64,65. Thus, the various peptides66, extracellular
vesicles67 and metabolites68,69 in plasma have key roles in
the inter-​organ communication that is likely to mediate
many of the effects of exercise. Supporting this concept,
we observed, in a 2019 study, that serum from volun-
teers who have undergone endurance exercise increases
GLUT4 expression in human adipocytes in vitro70 com-
pared with serum from unexercised volunteers. A key
future challenge will be attaining a complete under-
standing of the full range of exercise-​induced factors,
their tissues of origin and their physiological relevance
to exercise adaptations.
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a
Gut
• Altered microbiome
Adipose tissue • Altered SCFA release Vascular system
• Enhanced substrate handling • Increased angiogenesis
• Altered adipokine secretion • Reduced atherosclerosis

Acute exercised and exercise-

Heart trained skeletal muscle
• Oxidative capacity Pancreas
• Altered morphology
• Myokines and extracellular • Enhanced β-cell function
• Improved cardiac function
vesicles
• Exercise-induced metabolites

Liver Brain
• Enhanced substrate handling • Improved cognition
• Enhanced insulin sensitivity Immune system • Enhanced mental health
• Altered hepatokine secretion • Reduced chronic
inflammatory state

b
Hierarchy of exercise Examples of exercise-sensitive
adaptive mechanisms potential therapeutic targets

Low High
• Catecholamines
Physiological stimulus
• Low energy balance

Potential therapeutic effect

On-target specificity
Intracellular signalling • AMPK
pathways • CaMKII

Epigenetic regulators Class IIa HDACs

• Nor1
Transcription factors
• PPARδ
and co-regulators
• MEF2 High Low

Exercise adaptive Enhanced oxidative

response capacity

Fig. 1 | Exercise adaptations and their theoretical therapeutic potential. a | Single bouts of exercise and exercise
training influences skeletal muscle oxidative capacity and induces the secretion of myokines, extracellular vesicles and
metabolites that facilitate crosstalk with other tissues. This crosstalk is thought to have positive effects on the function
of major systems and organs, including the brain, heart, liver, pancreas, adipose tissue, gut, and the immune and vascular
systems. b | Exercise imparts physiological stimuli or stressors that activate a complex array of intracellular signalling
pathways. Some of these pathways signal to epigenetic regulators, transcription factors and transcriptional co-​regulators
that precisely control transcriptional responses and the adaptive response to exercise. Therapeutically targeting
physiological stimuli that mediate the responses to exercise might induce a large proportion of the molecular responses
to exercise and have high theoretical therapeutic efficacy; however, such targets can have low on-​target therapeutic
specificity. That is, undesirable effects ensue when this target is engaged in the absence of the exercise stimulus in its
entirety. By contrast, targeting exercise-​associated transcriptional regulators has a fairly high on-​target therapeutic
specificity but might mediate only a small fraction of the exercise adaptive response and therefore have only low
therapeutic efficacy. AMPK, AMP-​activated protein kinase; CaMKII, calcium–calmodulin dependent protein kinase II;
HDACs, histone deacetylases; MEF2, myocyte enhancer factor 2; Nor1, nuclear receptor NR4A3; PPARδ, peroxisome
proliferator activated receptor-​δ; SCFA, short-​chain fatty acid.

Exercise-​induced transcription altered transcription and translation as well as in post-

As described earlier, exercise results in numerous adap-
tations in multiple tissues and organ systems. A key
adaptation is the increased expression of vari­ous pro-
teins and changes in their activation state and locali­
zation as part of fundamental molecular and cellular
processes. The vari­ous signals generated during exercise
activate multiple signalling pathways that result in
transcriptional and post-translational modifications7.
A paradigm has emerged over the past 20 years that tran-
sient increases in the levels of mRNA of vari­ous meta-
bolic, myogenic and regulatory genes occur in response
to successive exercise bouts, which leads to increased
protein expression and improved functional capacity2,4.
This paradigm was based on observations that a single

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bout of exercise increased transcription and the mRNA
levels of selected genes in skeletal muscle71–74. Subsequent
studies in both rodents and humans have undertaken
more detailed time-​course analyses of exercise-induced
changes in mRNA and protein levels as well as enzy-
matic functional activity in skeletal muscle following
short-​term training over 1–2 months and confirmed
the importance of transcriptional events for adaptation
during and after exercise75,76. That said, these findings in
no way diminish the role of post-transcriptional, trans-
lational and post-​translational events or the effects on
protein turnover and stability; these processes are just as
important, if not more so, in facilitating exercise adap-
tations in skeletal muscle77. Furthermore, the accurate
assessment of exercise adaptation requires more than just
the measurement of mRNA levels78. Nevertheless, the
study of transcriptional responses to exercise and
the associated signalling and downstream molecular
events does provide key insights on the molecular basis
of skeletal muscle adaptations to exercise.
Epigenetic mechanisms of exercise adaptation. Alterations
in gene expression require the regulation of epigenetic
machinery and the remodelling of chromatin (Box 1)
to a transcriptionally permissive state. The epigenetic
mechanisms currently known to be regulated by exercise
include DNA methylation state and modifications to his-
tone proteins, and have been reviewed elsewhere79,80. The
methylation of cytosine residues within DNA is generally
associated with transcriptional repression. Methylation
mediates this repression either by impairing the DNA
binding ability of transcription factors with GC-​rich
consensus binding sequences or by altering the chroma-
tin architecture so that it favours a compacted structure
associated with transcriptional silencing81.
DNA methylation was generally thought to be a
fairly stable modification; however, global DNA methy­
lation is rapidly decreased in human skeletal muscle
within 45 min after exercise82. Furthermore, decreased
methylation of the promoter regions of certain exercise-
responsive genes that are important for oxidative
capacity (including Ppargc1a, PPARδ, TFAM and
MEF2A) was observed immediately following exercise
Box 1 | The importance of chromatin architecture
Eukaryote DNA is wrapped around a core of histone proteins, which together are
referred to as a nucleosome. Each nucleosome consists of 147 base pairs of DNA,
wrapped ~1.65 times around an octamer of histone proteins148. These nucleosomes
occur in repeating units to form chromatin and the larger chromosomes that help
compact and organize the vast amount of genetic material in eukaryote cells148.
Chromatin architecture has a key role in regulating gene transcription. Highly
compacted chromatin is associated with transcriptional silencing as transcriptional
activators cannot gain access to the gene regulatory and coding regions of DNA88.
However, the decompaction of chromatin reveals these DNA regions to transcriptional
regulators and is associated with transcriptional activation149. A number of factors
influence the structure of chromatin, including the methylation of cytosine residues
in DNA and post-​translational modifications of histone proteins, which are together
referred to as epigenetic modifications150. These modifications can be stable or highly
dynamic to control both steady state151 and pulsatile transcriptional kinetics152,
respectively. These mechanisms are highly coordinated by numerous epigenetic
enzymes, transcription factors and upstream signalling pathways to provide precise
control over specific transcriptional programmes.
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and was associated with their increased expression
in human skeletal muscle82. Of note, the removal of
methyl groups from cytosine nucleotides requires
the catalytic action of ten-eleven translocation (TET)
dioxygenase DNA demethylation enzymes83. Although
decreased DNA methylation has been associated with
increased expression of exercise-​responsive genes,
mechanistic corroboration of the role of DNA hypo-
methylation in the exercise-​induced transcriptional
response remains to be established. Nonetheless, these
data provide the rationale for further investigations of
the TET enzymes as mediators of the exercise-​induced
transcriptional response.
Post-​translational modifications to histone proteins
have a substantial influence on chromatin structure and
gene expression, and have been extensively reviewed
elsewhere84–86. One such modification is acetylation.
Exercise is associated with the acetylation of various
lysine residues within histone proteins in human skele­
tal muscle87, a modification that is generally asso­ciated
with decompaction of chromatin and activation of
transcription88. Indeed, the acetylation of lysine 9 and 14
within the Glut4 promoter is associated with increased
expression of the Glut4 gene in rat skeletal muscle
immediately following swimming exercise89. Of note, the
acetylation state of histones is controlled by the reciprocal
actions of histone acetyltransferases (HATs) and histone
deacetylases (HDACs)90. Our own work, as well as
that of others91,92,93,94, has established that the class IIa
HDACs have a key role in the transcrip­tional response
to exercise. For example, in human skele­tal muscle
following 60 min of cycling exercise, the class IIa HDACs
are phosphorylated and exported from the nucleus, which
is associated with histone acetylation and the expression
of exercise-​responsive genes91,92. Furthermore, in mouse
skeletal muscle, transient expression of a HDAC5 mutant
that cannot be phosphorylated and exported from the
nucleus prevents the expression of exercise-​responsive
gene Ppargc1a 93. Similarly, we have shown that
overexpression of class IIa HDAC mutants that cannot
recruit a functionally essential co-repressor complex
results in an exercise-like transcriptional response94. These
data suggest that the regulation of class IIs HDACs is an
essential component of the adaptive response to exercise.
The identity of the HAT enzymes responsible for his-
tone acetylation in response to exercise has been more
elusive. Three major HAT families, the GNTA, MYST and
p300/CBP families95, acetylate histones and non-​histone
proteins. The activity and genomic localization of these
three HAT families are controlled by distinct signalling
mechanisms96. Interestingly, loss-​of-​function mouse
models for p300 and GCN5, which represent major iso-
forms from two of the three HAT families, show no differ-
ence in metabolic adaptions to exercise when compared
with wild-​type mice97,98. This finding could suggest that
other HAT enzymes are more important or, alternatively,
that extensive redundancy exists in HAT signalling.
Exercise adaption mechanisms at the transcriptional
level. Specificity in the activation of transcriptional pro-
grammes is mediated by DNA binding transcription
factors99. They play a key role in coordinating epigenetic
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Reviews
Type II fibres
Muscle fibres that are fast
twitch, are able to produce
large amounts of tension,
have a fairly high reliance
on anaerobic ATP production
and fatigue easily.
500 | September 2020 | volume 16 www.nature.com/nrendo
responses at distinct genomic loci, which is mediated
through sequence-​specific DNA binding preferences100.
Transcription factors recruit and interact with both tran-
scriptional activators and repressors and play a key part
in linking distal gene enhancers with target genes by
regulating the higher-​order chromatin architecture101,102.
These factors are also essential for recruitment of the
transcriptional initiation complex, which includes RNA
polymerase II, to regions of decompacted chromatin101.
Numerous transcription factors have been identi-
fied as important in coordinating aspects of the exercise
adaptive response. For example, nuclear hormone recep-
tors are important regulators of muscle phenotype, and
their role in the adaptive response to exercise has been
extensively reviewed elsewhere103. The nuclear hormone
family includes transcription factors that are activated
by lipid ligands such as the peroxisome proliferator acti-
vated receptors (PPARs). Of note, the PPARδ (otherwise
known as PPARβ) and PPARγ isoforms are important
for oxidative metabolism adaptations historically asso-
ciated with endurance exercise, whereas the PPARα iso-
form seems to be important for metabolic adaptations
in type II fibres103.
Meta-​analyses of transcriptomic datasets from
human and mouse studies of both aerobic and resistance
exercise revealed the nuclear receptor NR4A3 (Nor1)
to be an important regulator of exercise adaptations,
independent of exercise modality104,105. This finding is
supported by studies in transgenic mice overexpressing
Nor1 in skeletal muscle. In the sedentary state, these
mice display an exercise training phenotype that is
characteristic of mixed exercise modalities, including
skeletal muscle hypertrophy, increased vascularisation
and improved endurance exercise performance106–108.
The myocyte enhancer factor 2 (MEF2) family of
transcription factors has also been implicated in reg-
ulating metabolic responses as well as muscle struc-
ture and function responses to exercise in mice and
humans92,94,109. Although this is not an exhaustive list
of exercise-​responsive transcription factors, it is inter-
esting to note that exercise-​responsive PGC1α is a
transcriptional co-​activator for all of the transcription
factors mentioned110–112. Similarly, class IIa HDACs are
the major regulators of MEF2 function by directly asso-
ciating with and repressing this family of transcription
factors113. These specific examples highlight how epige-
netic enzymes are recruited to distinct gene regions to
control specific transcriptional programmes.
As mentioned earlier, the activity of these epigenetic
regulators and transcription factors is controlled by
post-​translational modifications, such as phosphor­
ylation and acetylation, that are regulated by exercise-
responsive signalling pathways. AMPK, which is
activated by a low cellular energy balance, is one of the
most extensively studied signalling molecules in the con-
text of exercise. Moderate intensity endurance exercise
activates skeletal muscle AMPK in humans12, which
regulates aspects of substrate metabolism114,115 and cal-
cium homeostasis34. In addition to these roles, AMPK
also translocates to the nucleus during exercise116 and
signals through a number of epigenetic regulators,
transcription factors and transcriptional co-​regulators
to activate metabolic transcriptional programmes117.
For example, during exercise, AMPK in the nucleus
can phosphorylate the class IIa HDACs, which results
in their nuclear export, histone acetylation and activa-
tion of MEF2-​dependent transcription118. AMPK also
phosphorylates histone 3 at serine 10, which is required
before it can be acetylated at lysine 9 (ref.119). Taken
together, these findings suggest that there is a highly
coordinated control of transcriptional programmes by
the energy-​sensing kinase AMPK.
CaMKII is also activated by exercise15 and selectively
phosphorylates HDAC4, which results in nuclear export
of both HDAC4 and HDAC5 owing to the hetero­
dimerization of these two class IIa HDAC isoforms120.
Pharmacological inhibition of CaMKII is sufficient
to prevent exercise-​induced histone acetylation at the
Glut4 promoter in rats89. AMPK and CaMKII are just
two examples of how exercise engages signalling path-
ways through perturbations in intracellular energy
and calcium homeostasis to control gene expression
responses in skeletal muscle. The complexities in the
signalling responses to exercise are yet to be completely
deciphered. However, as multiple omics approaches are
becoming more accessible, it is anticipated that further
signalling mechanisms linking exercise with transcrip-
tional control will emerge. These data will probably be a
rich resource for potential targets to recapitulate aspects
of the exercise adaptive response.
Therapeutic targets revealed by exercise
A mechanistic understanding of the hierarchical mecha­
nisms controlling the adaptive response to exercise has
started to yield potential targets for therapeutic inter-
ventions that increase oxidative capacity and provide
other exercise-​like health benefits. An important consi­
deration when selecting targets for such a strategy is
the relative trade-​off between potential therapeutic
efficacy and specificity, assuming systemic pharmaco-
logical administration (Fig. 1b). For example, targeting
a physiological stimulus, such as catecholamines, will
recapitulate a large proportion of the exercise adaptive
response in skeletal muscle; however, such a strategy will
have other undesirable effects such as increased hepatic
glucose output, hypertension and pathological cardiac
hypertrophy. These ‘on-​target’ effects become undesira-
ble in the absence of other specific responses to exercise;
for example, elevated skeletal muscle glucose uptake
that requires increased hepatic glucose output or the
increased oxygen requirement of skeletal muscle induced
by exercise that manipulates cardiac hypertrophy signals
into a physiological cardiac hypertrophy phenotype. By
contrast, targeting specific transcriptional mechanisms
might increase on-​target specificity but engage only a
small fraction of the exercise adaptive response, which
reduces the potential therapeutic efficacy.
At present, the highly complex physiological
responses to exercise seem impossible to replicate in
their entirety by pharmacological means. Furthermore,
it is unlikely that any one drug will be able to repli-
cate the entire adaptive response to exercise owing to
the trade-​off between specificity and efficacy (Fig. 1b).
This concept will be further discussed in the following

proof-​of-​concept examples, whereby molecules regu-
lated by exercise have been targeted pharmacologically
for therapeutic gain. In addition, the pharmacokinetics
of potential therapies and their ability to mimic the
pulsatile nature of exercise-​induced signalling and
transcriptional responses will also be addressed.
Targeting AMPK signalling. The involvement of AMPK
in the transcriptional response to exercise as well as in
substrate uptake and utilization after exercise makes it an
obvious target for exercise-​like therapeutic interventions.
Early studies utilized 5-​aminoimidazole-4-​carboxamide
riboside (AICAR), a compound that activates AMPK
in a manner similar to AMP121. Daily subcutaneous
administration of AICAR to rats for 4 weeks increased
the abundance of mitochondrial enzymes in type II mus-
cle fibres as well as other exercise-​responsive metabolic
proteins, such as GLUT4, in all muscle fibre types122.
It was later revealed that this AICAR-​associated effect
was largely driven by activation of a transcriptional
programme encoding these mitochondrial enzymes
and GLUT4 (ref.123). Both of these studies highlighted
that, although AMPK activation replicated some of the
skeletal muscle adaptive responses to exercise, it did not
replicate all of them.
The development of highly specific AMPK agonists
has enabled more robust assessment of AMPK as a thera­
peutic target. In particular, studies of the small mole-
cule MK-8722, which is a direct allosteric activator of
AMPK124, have been particularly revealing. For example,
acute administration of a single dose of MK-8722 to
mice induces a transcriptional response that is highly
similar to the response to a single bout of exercise in a
range of tissues, including skeletal muscle, heart, liver
and adipose tissue125. Furthermore, ontology analysis
showed that this transcriptional response was enriched
for genes involved in mitochondrial biogenesis, fatty acid
oxidation, glucose uptake and insulin action125. Chronic
administration of MK-8722 for 1 month in obese mice
had exercise-​like effects on glucose homeostasis124.
Of note, MK-8722 has also had positive efficacy in a
rat model of chronic kidney disease, which is possibly
related to these positive effects on glucose homestasis126.
However, chronic administration of the drug also
resulted in cardiac hypertrophy, which is an undesirable
effect thought to be secondary to the accumulation of
glycogen in the heart124, presumably as a result of unre-
strained glucose uptake. Similarly, mice with a mutation
in the γ subunit of AMPK resulting in cons­titutive activa-
tion of AMPK, show a fatal hypertrophic cardiomyopa-
thy22,23,127. This finding highlights the pitfalls of increasing
substrate uptake by tissues without a concomitant increase
in energy expenditure and is an example of the trade-​off
between therapeutic efficacy and on-​target specificity.
Attempts to address the trade-​off between effi-
cacy and specificity have been made by manipulating
the meta­bolic properties of MK-8722. For example,
MK-8722 analogues were synthesised with pharma-
cokinetics that were more similar to the transient and
pulsatile nature of the exercise response125. These
shorter-​acting MK-8722 analogues retained the ability
to reduce hyperglycaemia in various rodent models of
NAture RevIewS | EnDoCrInology
Reviews
obesity and, importantly, did not result in the accumu­
lation of cardiac glycogen or cardiac hypertrophy125. This
study emphasizes the importance of designing therapies
with pharmacokinetics similar to the pulsatile nature of
exercise-​induced signalling.
Targeting nuclear receptors. Focusing on potential
exercise-​associated transcriptional targets rather than
on signalling pathways has yielded interesting observa-
tions. Nuclear receptors are obvious molecular targets
to replicate aspects of the exercise adaptive response,
particularly given their ligand-​specific requirements
for activation, meaning that these transcription factors
are highly druggable with small molecules. The PPARδ
agonist GW501516 has received considerable interest
for its potential to activate exercise-​like transcriptional
programmes. For example, chronic administration
of GW501516 for 5 weeks in mice induced a skeletal
muscle transcriptional programme that showed an
~50% overlap with that of endurance exercise train-
ing, comprising genes involved in lipid and mitochon-
drial metabolism123. Increasing the dose of GW501516
(ref.128), combining GW501516 with exercise training
or administering GW501516 with AICAR123 potenti-
ated these effects and induced many of the hallmark
features of endurance exercise training. Furthermore,
GW501516 had positive effects on glucose homeostasis
and other metabolic parameters in mouse models of
obes­ity and the metabolic syndrome129–131, highlight­
ing  the potential for therapeutic utility. However,
whether these effects are mediated by skeletal muscle
or other tissues, such as liver, adipose tissue or intestine,
remains to be determined132,133.
GW501516 has also been touted as a potential therapy
for Duchenne muscular dystrophy owing to its activation
of genes involved in both oxidative capacity and muscle
structure and function134. However, this compound was
ultimately withdrawn from clinical development owing
to its propensity to induce the formation of colorectal
adenomas, which has been ascribed to PPARδ function135.
However, this is an area of controversy as GW501516 and
another structurally related synthetic PPARδ agonist,
GW0742, are reported to have anticancer activity in naso-
pharyngeal and skin carcinoma cells, respectively136,137.
Whether the divergent effects on tumorigenesis can be
ascribed to cell type-​specific PPARδ-​dependent tran-
scriptional programmes or whether they are a result
of more complex interactions with different transcrip-
tional co-​repressors or co-​activators in different cell types
remains to be determined. Nevertheless, these discrepant
findings highlight potential problems with undesirable
on-​target effects in tissues other than skeletal muscle
when compounds designed to replicate aspects of the
skeletal muscle exercise adaptive response are adminis-
tered systemically. Indeed, consideration of the action of
a molecule in other tissues should be prioritized when
selecting targets for therapeutic intervention.
Targeting HDAC complexes. Our own work has focused
on modulating the MEF2–class IIa HDAC pathway
in order to induce phenotypic adaptations in skeletal
muscle (Fig. 2). The class IIa HDACs are catalytically
volume 16 | September 2020 | 501
Reviews

a Fig. 2 | The MEF2–class IIa HDAC axis as a target to

replicate aspects of the exercise adaptive response.
a | At rest, myocyte enhancer factor 2 (MEF2) activity is
repressed by the class IIa histone deacetylases (HDACs),
which recruit a co-​repressor complex containing SMRT,
HDAC3 NCor1 and HDAC3 that keeps the surrounding chromatin
in a condensed state. b | During exercise, AMP-​activated
NCor1 SMRT
protein kinase (AMPK) is activated and translocates to the
nucleus, phosphorylating the class IIa HDACs, resulting
HDAC4 HDAC5
in their nuclear export. This disrupts the class IIa HDAC
MEF2 co-​repressor complex, resulting in histone acetylation
(Ac) and MEF2-​dependent transcriptional activation.
Gene c | Pharmacological targeting of the MEF2-​class IIa HDAC
expression axis with Scriptaid also disrupts the class IIa HDAC
co-repressor complex, resulting in histone acetylation
and MEF2-​dependent transcriptional activation and an
exercise-​like transcriptional response.

Nucleus
inactive against acetyl-​lysine due to a single amino acid
substitution in their active site138, which means that
they are a poor target for traditional HDAC inhibi­
tors designed to inhibit HDAC activity. The ability
b of class IIa HDACs to repress MEF2-​dependent gene
expression requires recruitment of a larger co-​repressor
complex that includes NCor1, SMRT and HDAC3
P (ref. 139) (Fig. 2a) . Exercise disrupts the interaction of
this co-repressor complex with the class IIa HDACs
AMPK Exercise following their phosphorylation and nuclear export91,92
HDAC3
(Fig. 2b); we therefore focused on identifying molecules
NCor1 SMRT that had similar effects. Importantly, the interaction
P P P P P P P P between the class IIa HDACs and SMRT occurs through
HDAC4 HDAC5 HDAC4 HDAC5
regions surrounding the class IIa HDAC active site140.
This information was used to identify molecules that
Ac can bind this site and have large structural capping
Ac
groups that protrude out of the active site and might
Gene
expression disrupt the molecular interactions that confer SMRT
Ac MEF2
Ac binding. This work identified Scriptaid as a molecule
Pol II that disrupts the interaction between HDAC5 and
SMRT94 (Fig. 2c).
A single administration of Scriptaid to wild-​type mice
induced an exercise-​like transcriptional response that
was dependent on an intact class IIa HDAC co-repressor
complex94. Furthermore, 4 weeks of Scriptaid admini­
c stration induced many of the hallmark pheno­t ypic
alterations observed with exercise training, including
HDAC3
an increased skeletal muscle oxidative capa­city and
improved exercise performance. In addition, 4 weeks
NCor1 SMRT of Scriptaid administration also increased whole-​body
energy expenditure and lipid oxidation and decreased
fasting blood concentrations of glucose and lipid
levels94. Scriptaid also had therapeutic effects in obese
Scriptaid
HDAC4 HDAC5 mice, increasing insulin-​stimulated glucose uptake into
skeletal muscle and improving cardiac function141. The
Ac
latter effect was an important observation as currently
Ac no therapies exist that can treat obesity-​associated
Gene cardio­myopathy. This finding was somewhat surpris-
Ac MEF2 expression ing considering the putative role of the class IIa HDACs
Ac
Pol II
in suppressing pathological cardiac hypertrophy142–144.
However, studies suggesting that the class IIa HDACs
suppress hypertrophy have been performed in mouse
models where class IIa HDACs have been deleted from
birth and could suggest that this family of HDACs have
divergent functions in the developing heart versus

502 | September 2020 | volume 16 www.nature.com/nrendo

 Reviews

the adult heart. Whether the efficacy of Scriptaid on Conclusions

cardiac function in obesity is due to its direct action
on the heart or is secondary to increased lipid disposal
and decreased circulating levels of lipid remains to
be determined.
In addition to its ability to disrupt class IIa HDAC
co-​repressor interactions, Scriptaid is also a selective
HDAC inhibitor against HDAC6. Although our studies
confirmed that Scriptaid exerts its metabolic transcrip­
tional effects by acting through the class IIa HDACs94,
HDAC6 is an important regulator of cytoskeletal and
proteasome function145. Therefore, Scriptaid lacks the
specificity to be used clinically. Nonetheless, these
studies provide another example where exploring the
bio­logy of exercise can reveal new preclinical thera­
peutic approaches to combat chronic diseases. These
data also highlight the value in identifying the speci­
fic molecular interactions involved in the adaptive
response to exercise, which might provide greater
thera­peutic specificity than simple agonist or antago-
nist approaches to modulate exercise-​responsive mole­
cules. Indeed, interest is growing in the activation of
these molecular mechanisms in order to engage adap-
tive responses that are induced by exercise146. That
said, given the diversity and complexity of the adaptive
responses to exercise, it is unlikely that a single agent or
even a combination (that is, a polypill) will fully recapit-
ulate these responses and their health and performance
consequences147.
Exercise has numerous health benefits that are due,
in part, to skeletal muscle adaptations that can influ-
ence metabolism and function in other tissues and at
a whole-​body level. The transcriptional response to a
single bout of exercise is important for the phenotypic
alterations of skeletal muscle in response to exercise
training, and studies have begun to unravel the complex
interactions between physiological stimuli, intracellular
signalling pathways, and epigenetic and transcriptional
mechanisms that control these responses. We have high-
lighted some of these mechanisms and proof-​of-​concept
examples, where exercise-​responsive molecules have
been targeted pharmacologically to induce exercise-​like
adaptive responses and some associated health benefits.
These examples show that it might not ever be possible to
faithfully mimic all of the complex molecular, physiolo­
gical and health effects of exercise; however, understand-
ing and pharmacologically harnessing the molecular
events engaged by exercise in skeletal muscle can still
deliver important health outcomes. Our understanding
of the molecular events and factors that respond to exer-
cise in skeletal muscle are still rudimentary. However,
this means that there will be copious opportunities to
further leverage this approach as our knowledge of the
molec­ular responses to exercise increases to combat
the raft of chronic diseases currently challenging society.
Published online 6 July 2020

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Acknowledgements
The authors acknowledge the many researchers whose work they
have not been able to cite in this Review. Original work by the
authors was supported by the Diabetes Australia Research Pro­
gram and the National Health and Medical Research Council
of Australia.
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
Both authors hold equity in Imitex Pty Ltd., a drug discovery
start-​up that was spun out from papers published by the
authors that have identified the MEF2-​class IIa HDAC axis as
a druggable target to replicate aspects of the exercise adap-
tive response. This pathway is discussed in the current manu­
script, along with many others that have been studied within
the field.
Peer review information
Nature Reviews Endocrinology thanks M.H. Laughlin and
M. Tarnopolsky for their contribution to the peer review of
this work.
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