Exp Physiol 101.

1 (2016) pp 17–22 17

Symposium Report

Adaptations of skeletal muscle mitochondria to exercise

training
Carsten Lundby1 and Robert A. Jacobs1,2,3
1
Zürich Center for Integrative Human Physiology, Institute of Physiology, University of Zürich, Zürich, Switzerland
2
Health and Physical Education, School of Teaching and Learning, Western Carolina University, Cullowhee, NC, USA
3
Physical Therapy Department, Western Carolina University, Cullowhee, NC, USA

New Findings
r What is the topic of this review?
We review recent work relating to exercise-induced alterations in mitochondrial structure and
function.
r What advances does it highlight?
Experimental Physiology

Training mitochondrial volume density increases due to 1) an increase cross sectional area and
2) longitudinal growth. Specific respiratory alterations appear dependent on exercise training
intensity. Low-moderate endurance training primarily improves the capacity for fat oxidation
whereas high-intensity interval training (HIT) improves global respiratory capacity. The latter
includes maximal state 3 mass-specific respiration, which is the strongest individual measure
predictive of endurance performance. This highlights the importance of training specificity
in endurance athletes.

Mitochondrial volume density (MitoVD ) is composed of two distinct mitochondrial

subpopulations— intermyofibrillar mitochondria (MitoIMF ) and subsarcolemmal mitochondria
(MitoSS ). With exercise training, MitoVD may increase by up to 40% and is, for the most part,
related to an increase in MitoIMF . Exercise-induced adaptations in mitochondrial function
depend on the intensity of training and appear to be explained predominately by an
increased expression of mitochondrial enzymes that facilitate aerobic metabolism. Although
mitochondrial content often increases with training, it seems that mitochondrial adaptations
are not needed to facilitate maximal oxygen uptake, whereas such adaptations are of greater
importance for endurance capacity.

(Received 31 July 2015; accepted after revision 24 September 2015; first published online 6 October 2015)
Corresponding author C. Lundby: University of Zurich, Institute of Physiology, Winterthurerstrasse 190, CH-8057
Zurich, Switzerland. Email: carsten.lundby@uzh.ch

Introduction The response of skeletal muscle mitochondria

The intent with this article (based on a talk by C.L. at the
20th Annual Congress of the European College of Sport
Science) is to address and examine recent work in the field
mitochondrial adaptations to exercise training. The topics
addressed are as follows. (i) How do mitochondria respond
to exercise training? (ii) What are the significances of these
adaptations in terms of exercise performance?
to exercise
Approximately 4–7% of skeletal muscle volume compises
mitochondria, referred to as skeletal muscle mitochondrial
volume density (MitoVD ). The MitoVD is composed of
two limited and distinct populations of non-connected
mitochondrial subpopulations. The more abundant
subpopulation, accounting for up to 80% of total MitoVD ,


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C 2015 The Physiological Society DOI: 10.1113/EP085319
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 18 C. Lundby and R. A. Jacobs
are intermyofibrillar mitochondria (MitoIMF ), which, as
indicted by the name, reside in between myofibrillar
sarcomeres (Fig. 1). Accordingly, this subpopulation is
primarily responsible for the bioenergetics sustaining
muscle contraction. The second and less pervasive
subpopulation consists of subsarcolemmal mitochondria
(MitoSS ) that exist just beneath the sarcolemma (Fig. 1).
The MitoSS work to sustain the bioenergetic demands of
active membrane ion and substrate transporters, which
help to maintain membrane potential and cytoplasmic
homeostasis, respectively (Hood, 2001). Mitochondrial
adaptations in response to exercise or sustained skeletal
muscle contractions are robust, but for the purposes of this
review we focus on the changes of specific mitochondrial
characteristics, including MitoVD , oxidative/respiratory
capacity, nutrient partitioning and electron coupling
efficiency.
Exercise stimulates an increase in total mitochondrial
protein (Holloszy, 1967; Scalzo et al. 2014), including
enzymes involved in β-oxidation, the tricarboxylic acid
cycle and the electron transport system (Holloszy,
1967; Baldwin et al. 1972; Jacobs et al. 2013c; Scalzo
et al. 2014). Accordingly, increases in skeletal muscle
oxidative or respiratory capacity also occur in response
to exercise training (Baldwin et al. 1972; Pesta et al.
2011; Jacobs et al. 2013c). In line with mitochondrial
protein expression and respiratory capacity, MitoVD can
increase up to 40% in response to endurance exercise
training (Hoppeler et al. 1985; Montero et al. 2015).
Structural changes and shifts in mitochondria are evident
after a single bout of exercise (Picard et al. 2013). These
exercise-induced biochemical and morphological changes
between mitochondrial subpopulations differ. Relative
changes (%) in MitoSS are more responsive than MitoIMF
LD
End Cap
IMF
SS
MF
2 1μm
Figure 1. Electron micrograph of human skeletal
muscleElectron microscopy image illustrating subsarcolemma
(SS) and intramyofibrillar (IMF) mitochondria. Abbreviations:
Cap, capillary; End, endomysium with collagen and elastin; LD,
lipid droplet; and MF, muscle fibre. Courtesy of Simone Fenk
from the laboratory of C.L.
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Exp Physiol 101.1 (2016) pp 17–22
to exercise (Krieger et al. 1980); however, absolute changes
() tend to be greater in MitoIMF . Given that the absolute
volume of MitoSS is much lower than that of MitoIMF , the
greater increase in MitoSS does not contribute as much
to the overall increase in MitoVD as does an increase in
MitoIMF (Hoppeler et al. 1985; Montero et al. 2015).
Evidence suggests that mitochondrial hypertrophy is
primarily responsible for exercise-induced increases in
MitoVD (Tarnopolsky et al. 2007). Furthermore, more
recent unpublished data (Carsten Lundby) from our
laboratory suggest that, overall, the initial increase in the
tube-like reticular network of the organelle is primarily
dependent on an increase in cross-sectional area; however,
once the cross-sectional area reaches a critical level, further
increases in MitoVD are the result of longitudinal growth,
i.e. much like when blowing up a cylindrical balloon
(Fig. 2).
The MitoVD is generally correlated with the percentage
of slow-twitch (type I) skeletal muscle fibres (Sjöström
et al. 1982). After endurance exercise training, however,
the increase in MitoVD is somewhat more pronounced in
type IIa when compared with type I or type IIx fibres
(Howald et al. 1985). Furthermore, higher MitoVD has
been observed in the deltoid, a predominantly fast-twitch
skeletal muscle, of highly trained cross-country skiers
compared with measures collected from the vastus lateralis
of untrained control subjects (Ortenblad et al. 2013). Thus,
exercise-induced augmentation of MitoVD is not overly
restricted by skeletal muscle fibre type, and changes appear
to be most adaptable in type IIa skeletal muscle fibres.
Interestingly, it is also fast-twitch skeletal muscle that
appears to be predisposed to age-induced impairments
in mitochondrial function (Jacobs et al. 2013b).
Exercise-induced improvements in skeletal muscle
oxidative capacity per milligram of tissue generally
parallel MitoVD expansion (Fig. 3A); however, this
association should be interpreted carefully. An increase
or decrease in skeletal muscle respiratory capacity is not
dependent on a complimentary alteration in MitoVD .
Inversely, a change in MitoVD does not inherently
suggest a corresponding modification in respiratory
capacity. We observed significant increases in skeletal
muscle MitoVD after 6 weeks of endurance training,
without any reciprocal improvements in skeletal muscle
complete state 3 respiratory capacity (Montero et al.
2015). Thus, it may be imprudent to interpret specific
mitochondrial modifications (i.e. increased MitoVD )
as a surrogate measure for another characteristic
(i.e. oxidative phosphorylation capacity). Mitochondrial
structure and function are so fluid and dynamic in
their response to bioenergetic stress that the validity of
static individual biomarkers may be lost over time (i.e.
in a repeated-measures model) when combined with
prolonged metabolic stress, i.e. exercise training and/or
hypoxia (Jacobs et al. 2012, 2013c). Conversely, in studies

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 Exp Physiol 101.1 (2016) pp 17–22 Mitochondria and exercise 19

where all samples are collected at one time point (i.e. Exercise-induced increases in skeletal muscle
independent-samples model, control versus treatment respiratory capacity appear to be explained predominately
groups; Jacobs et al. 2013a,b; Jacobs & Lundby, 2013) by an increased expression of mitochondrial enzymes
it may be more appropriate to rely on these validated that facilitate aerobic metabolism (Schwerzmann
mitochondrial biomarkers (Larsen et al. 2012). et al. 1989; Jacobs et al. 2013c). Increases in specific

Initial
shape

50

25
ΔMitoLD (%)

First
0 modifications
- Hypertrophy -
–25

–50
50 100 150
Δ MitoVD (%)

Continous modifications
- Elongation -

Figure 2. Contribution of mitochondrial hypertrophy and length density (MitoLD ) to mitochondrial

volume density (MitoVD) expansion
The data suggest that the initial increase in MitoVD with exercise training is due to mitochondrial
hyperthrophy/swelling, whereas when a certain level of hypertrophy is reached the MitoVD is then further
increased primarily by augmenting MitoLD . Length expansion becomes progressively more important as
mitochondrial expansion continues, such as when blowing up a cylindrical balloon.

A B C
200 100 8
OXPHOS (pmol O2 sec–1 mg–1)

VO2max (I min–1 kg–1)

80
150 6
VO2max (I min–1)

60
100 4
40

50 2
20

0 0 0
0 5 10 0 2 4 6 8 10 12 0 2 4 6 8 10 12
MitoVD (%) MitoVD (%) MitoVD (%)

Figure 3. Association between mitochondrial volume density (MitoVD ), skeletal muscle respiratory
capacity and maximal oxygen uptake (V̇O2 max )
A, association between MitoVD (expressed as a percentage) and mitochondrial oxidative capacity of
permeabilized skeletal muscle fibres (OXPHOS; in picomoles of oxygen per second per milligram).
Statistical analysis: Pearson r = 0.6371, P value (two-tailed) < 0.0001. The correlation is significant
(α = 0.05), r2 = 0.4059. B and C, correlations between MitoVD (expressed as a percentage) and maximal
oxygen uptake as relative (litres per minute per kilogram; B) and absolute values (litres per minute; C)
in 66 individuals. Correlational analysis revealed a significant association between MitoVD and relative
V̇O2 max [Pearson r = 0.5925; P value (two-tailed) < 0.0001. The correlation is significant (α = 0.05),
r2 = 0.3511], whereas no statistical correlation was found for absolute V̇O2 max [Pearson r = 0.1770;
P value (two-tailed) = 0.1552. The correlation is not significant (α = 0.05), r2 = 0.03132]. All data have
been derived from various unpublished studies (Carsten Lundby) performed in the laboratory of C.L.


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 20 C. Lundby and R. A. Jacobs Exp Physiol 101.1 (2016) pp 17–22

substrate-stimulated respiratory capacity, however, do
not appear to be constant across all electron-accepting
components of the electron transport system. Moreover,
the specific alterations in the electron transport system
appear to be dependent on the intensity of exercise.
Maximal electron flow through electron-transferring
flavoprotein, the capacity for fat-stimulated respiration,
appears to improve the most with exercise training (Pesta
et al. 2011), and this improvement (25%) is independent
of training intensity, i.e. high-intensity interval (HIT) and
endurance training alike (Jacobs et al. 2013c; Montero et al.
2015). The second most responsive change in respiration
following exercise training is complete non-coupled
state 3 respiration (electron transport system capacity).
This respiratory state is achieved with saturating and
convergent electron input from electron-transferring
flavoprotein as well as both mitochondrial complexes I
(NADH dehydrogenase) and II (succinate dehydrogenase)
while in the presence of the proton ionophore carbonyl
cyanide p-(trifluoromethoxy) phenylhydrazone. This
respiratory state is commonly referred to as electron
transport system respiratory capacity and functions
independently from ATP synthase activity, with the inner
mitochondrial membrane potential completely collapsed
and an open or unimpeded transmembrane proton
circuit flowing through mitochondrial complexes I–IV.
This electron transport system respiratory state increases
(by 25%) much more in response to HIT (Jacobs
et al. 2013c), whereas typical endurance training shows
much less improvement, i.e. a non-significant 9%
increase (Montero et al. 2015). Interestingly, although
peak oxygen uptake (V̇O2 peak ) improves in response
to each exercise modality to a similar extent (8%),
those improvements are primarily attributed to different
physiological adaptations. Improvements in exercise with
HIT were primarily attributed to improvements in skeletal
muscle respiratory capacity (Jacobs et al. 2013c), whereas
improvements attendant to more common endurance
training were predominantly determined through
haematological adaptations (Montero et al. 2015). Given
this information, it is apparent that improvements in
skeletal muscle respiratory capacity occur with exercise
(Fig. 4), and the predominant change is the improved
ability to oxidize fat as a substrate. However, specific

Caloric Exercise Hypoxia

Restriction

Calcium Bioenergetic Strain Oxidative Stress

Ca
2+ AMP/ATP GSSG/GSH
ADP/ATP H2O2
NAD+/NADH O2-
˜

p38
CaMks AMPK SIRTs
MAPks

PGC-1α

MEF-2

Mitochondria
ERRs NRF-1 PPARs oxidative capacity
fatty acid oxidation
mtDNA gene transcription,
replication, & translation
NRF-2 mt hypertrophy
mt protein expression
TFAM MnSOD / SOD2

Figure 4. Schematic overview of signalling pathways facilitating mitochondrial alterations

Summary of signalling pathways that ultimately alter mitochondrial physiology in human skeletal muscle.
In general, there are three primary extracellular stimuli (i.e. caloric restriction, exercise and hypoxia) that
lead to cytosolic changes (ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine
triphosphate; GSSG/GSH, oxidized/reduced glutathione; H2 O2 , hydrogen peroxide; NAD+ /NADH,
oxidized/reduced nicotinamide adenine dinucleotide; O2 − , superoxide), which activate/upregulate
specific enzymes (AMPK, AMP-activated kinase; CaMKs, calcium–calmodulin-activated kinases;
p38MAPKs, p38 mitogen-activated protein kinases; SIRTs, sirtuins) that all stimulate a master regulator
of mitochondrial regulation (PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α),
which then stimulates/increases transcriptional activity of nuclear promoters in the nucleus (ERRs,
oestrogen-related receptors; MEF-2, myocyte enhancer factor-2; NRFs, nuclear respiratory factors 1 and 2;
PPARs, peroxisome proliferator-activated receptors) in addition to another nuclear encoded factor, which
then translocates into the mitochondria (Tfam, nuclear-encoded mitochondrial transcription factor A),
ultimately resulting in mitochondrial adaptations that are specified in the lower right-hand comer of
the illustration (MnSOD/SOD2, manganese superoxide dismutase; mtDNA, mitochondrial DNA).


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 Exp Physiol 101.1 (2016) pp 17–22
improvements along the electron transport system do
vary and appear to be dependent on the intensity of
exercise training.
What is the physiological significance of skeletal
muscle mitochondrial adaptations in relation to
exercise performance?
Early pioneering work by Ewald R. Weibel, Hans Hoppeler
and colleagues demonstrated a strong correlation between
V̇O2 peak and MitoVD across all species (Hoppeler et al.
1973, 1985; Weibel et al. 1991), and ever since then a high
MitoVD has been associated with a high exercise capacity
(Fig. 3). The positive association between MitoVD and
relative V̇O2 peak (in millilitres per minute per kilogram
body weight; Fig. 3B) is lost when expressed against
absolute V̇O2 peak (in millilitres per minute). Given that the
capacity for skeletal muscle oxidative respiration outstrips
the capacity for systemic O2 transport (Boushel et al.
2011), one may wonder why mitochondria adapt to
exercise training at all. Healthy volunteers undergoing
6 weeks of endurance training expanded their MitoVD
by 46% of which had no influence on V̇O2 peak when
exercise-induced increases in red blood cell volume were
withdrawn (Montero et al. 2015). Mitochondria appear to
adapt and compensate specifically to the type of metabolic
stress applied throughout exercise. With more common
endurance training, i.e. 60 min at 65% of peak power
output (Montero et al. 2015), the functional significance
of increases in MitoVD are most likely to reflect an
improved capacity to oxidize fat and thereby save limited
carbohydrate stores from becoming depleted (Brooks
& Mercier, 1994). Conversely, intense exercise training,
i.e. repeated 60 s efforts of high-intensity cycling at a
workload corresponding to the peak power, induces global
improvements in respiratory capacity (Jacobs et al. 2013c).
Identification of different alterations in mitochondrial
function in response to different exercise stimuli is
imperative for everyone interested in optimal exercise
performance. Mass-specific skeletal muscle respiratory
capacity has been identified as the best determining
factor of endurance performance in humans (Jacobs
et al. 2011). Consequently, these data highlight the
importance of altering intensity and/or duration within an
exercise training programme, particularly when training
for endurance events, in order to maximize skeletal muscle
mitochondrial function and overall exercise performance.
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Additional information
Competing interests
None declared.
Author contributions
The manuscript was drafted by both authors and both
authors have approved the final version of the manuscript
and agree to be accountable for all aspects of the work. Both
persons designated as authors qualify for authorship, and
all those who qualify for authorship are listed.
Acknowledgements
The authors wish to acknowledge all students, staff and
collaborators from the University of Zürich who have
contributed to our understanding of mitochondrial physiology
over the years.

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