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First published online May 26, 2006
Journal of Experimental Biology 209, 2239-2248 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02149
Review Article: Phenotypic Plasticity in Skeletal Muscle |
Functional, structural and molecular plasticity of mammalian skeletal muscle in response to exercise stimuli
Unit for Functional Anatomy, Department of Anatomy, University of Berne, Baltzerstrasse 2, Switzerland
e-mail: flueck{at}ana.unibe.ch
Accepted 6 February 2006
Summary
Biological systems have acquired effective adaptive strategies to cope with physiological challenges and to maximize biochemical processes under imposed constraints. Striated muscle tissue demonstrates a remarkable malleability and can adjust its metabolic and contractile makeup in response to alterations in functional demands. Activity-dependent muscle plasticity therefore represents a unique model to investigate the regulatory machinery underlying phenotypic adaptations in a fully differentiated tissue.
Adjustments in form and function of mammalian muscle have so far been characterized at a descriptive level, and several major themes have evolved. These imply that mechanical, metabolic and neuronal perturbations in recruited muscle groups relay to the specific processes being activated by the complex physiological stimulus of exercise. The important relationship between the phenotypic stimuli and consequent muscular modifications is reflected by coordinated differences at the transcript level that match structural and functional adjustments in the new training steady state. Permanent alterations of gene expression thus represent a major strategy for the integration of phenotypic stimuli into remodeling of muscle makeup.
A unifying theory on the molecular mechanism that connects the single exercise stimulus to the multi-faceted adjustments made after the repeated impact of the muscular stress remains elusive. Recently, master switches have been recognized that sense and transduce the individual physical and chemical perturbations induced by physiological challenges via signaling cascades to downstream gene expression events. Molecular observations on signaling systems also extend the long-known evidence for desensitization of the muscle response to endurance exercise after the repeated impact of the stimulus that occurs with training. Integrative approaches involving the manipulation of single factors and the systematic monitoring of downstream effects at multiple levels would appear to be the ultimate method for pinpointing the mechanism of muscle remodeling. The identification of the basic relationships underlying the malleability of muscle tissue is likely to be of relevance for our understanding of compensatory processes in other tissues, species and organisms.
Key words: exercise, endurance, hypoxia, gene, transcriptome, morphometry, microarray, PCR
Introduction
Skeletal muscle's malleability, which enables remodeling of the muscle's
structural makeup according to alterations in demand, is a particularly
striking phenomenon in the animal kingdom. This plasticity is reflected by the
pronounced adjustments seen in muscular force, endurance and contractile
velocity of mammalian skeletal muscle as a result of an alteration in demand
(Booth and Baldwin, 1996
). This
guise is widely recognized in sports, where distinct adaptation of muscle
tissue after training in athletes leads to striking phenotypic modifications
that maximize the specific performance of this contractile tissue.
One notable facet of skeletal muscle plasticity is the specificity of the
adaptive response to a given stimulus
(Fluck and Hoppeler, 2003),
where the degree of loading and the number of muscular contractions appear to
be the dominant stimuli for the muscular adaptations. For instance, highly
repetitive, low-load exercise training will cause differentiation of muscle
fibers towards a fatigue-resistance phenotype
(Pette, 2002). This cellular
specialization allows the recruited muscle fibers to sustain a high number of
slow contractions. Conversely, exercise regimes involving a high degree of
loading provoke an increase in force via fiber hypertrophy. By
contrast, maintenance of both skeletal muscle mass and oxidative capacity are
dependent on the impact of contractile stimuli, as shown by the pronounced
deconditioning of muscle function with inactivity. Thus the profile of muscle
perturbation exerts essential control over the muscle phenotype. This review
sets out our recent findings that build the case for the important involvement
of gene expression in ameliorations of muscle function with repetitive
exercise stimuli.
Mechanisms underlying myocellular adaptations to endurance training
The cellular and functional mechanisms underlying the particular
adaptations of the composite muscle tissue to endurance exercise are now well
understood. The cellular processes behind muscle plasticity involve
qualitative and quantitative alterations in muscle fiber cells and associated
structures. Alterations to endurance training over a period of weeks to months
involve differentiation of the muscle fibers towards a phenotype with a high
mitochondrial volume density (Fluck and
Hoppeler, 2003). These myocellular improvements are assisted by an
increase in capillary density and may involve a shift of the contractile
character of the fibers towards a slow type via an exchange of
sarcomere components (Fluck and Hoppeler,
2003). Collectively, these linked adjustments contribute towards
maximization of substrate delivery, respiratory capacity and contractile
parameters during the frequent slow contractions that occur with
endurance-type exercise.
The regulatory mechanisms underlying the specific adjustments of muscular
organelles to exercise are beginning to be unravelled. The data support the
notion that gene expression underlies muscular adjustments in response to
physical activity (Fig. 1). The
model suggests that individual homeostatic perturbations provoked by exercise
are integrated into alterations in expression levels of diffusible gene copies
(i.e. mRNAs), leading to translation of the encoded proteins by the ribosomal
machinery. Enhanced levels of gene transcripts would therefore support the
synthesis of protein components and provoke structural remodeling and
functional adjustments in the long term. Thus changes in mRNA act as a
blueprint for adjustment of protein composition (for reviews, see
Fluck et al., 2005a;
Fluck and Hoppeler, 2003;
Booth and Baldwin, 1996). In
this manner, exercise is known to specifically affect the rate of synthesis
(transcription) and degradation of gene transcripts
(Yan et al., 1996;
Fluck and Hoppeler, 2003). Gene
expression is therefore an important layer of processing for integration of
exercise stimuli into the adjustments of muscle makeup necessary to match
muscle function to alterations in demand.
|
To test this basic concept we set out to investigate the
post-transcriptional processes underlying the tuning of muscle metabolism upon
endurance training. The focus of analysis was on key factors of carbohydrate
and lipid metabolization, since these molecule classes constitute the main
substrates of skeletal muscle (Holloszy
and Coyle, 1984; van Loon et
al., 2001). Both of these organic compounds are imported from the
capillary bed via facilitative processes into the myocellular
compartment. There they reside as myocellular stores until they are subjected
to controlled metabolization to generate their energy equivalents (see
Fig. 2). During the catabolic
reaction, carbohydrates in the form of glucose are primarily degraded
via anaerobic glycolysis to pyruvate, and eventual complete oxidative
combustion in the mitochondria via the Krebs cycle. Similarly,
triglyceride-derived free fatty acids are imported into mitochondria where
they are combusted via beta-oxidation and the Krebs cycle. This
latter process produces carbon dioxide and supplies reduction equivalents that
lead to ATP production via coupling to oxidative phosphorylation. The
ATP generated during mitochondrial respiration is then used to drive
energy-dependent processes such as contractions
(Fig. 2). From a calorific
perspective, the aerobic processes within mitochondria are more efficient in
generating ATP than the anaerobic processes. This relates to the principal
implication of oxidative processes in energy allocation with sustained,
submaximal types of exercise (Jeukendrup,
2002).
|
The strategy employed to unravel the regulation of metabolic processes
involved parallel assessment of expression, structural and functional
parameters in a major recruited muscle group in two `steady states':
endurance-trained and untrained subjects, in order to reveal the biological
relationships that drive the muscle's response to repeated endurance exercise.
Oxidative metabolism measurements included the determination of mRNA levels
for factors necessary for relevant steps of mobilization and oxidative
metabolization of fatty acid in mitochondria as well as mitochondrial volume
densities (Fig. 2). Alterations
characterized in the heavily recruited vastus lateralis muscle demonstrated
that mitochondrial respiratory factors are concomitantly enhanced in
endurance-trained athletes (Puntschart et
al., 1995). These adjustments in transcript expression were in
proportion to the augmented mitochondrial volume density and the increase in
systemic maximal oxygen uptake seen in the athletic population compared to
untrained controls (Fig. 3A).
Note that both mitochondrial- and nuclear-encoded transcripts were increased
in a corresponding fashion. Thus mRNA levels of major mitochondrial
respiratory subunits are significantly correlated with mitochondrial volume
density (Fig. 4), suggesting
that local adaptations of mitochondrial transcript number in a major
locomotory muscle group are co-regulated, and matched to maximal respiration
of the system (i.e. VO2max) during
exercise.
|
|
).
Further exploratory correlation analysis uncovered significant relationships
between the two main lipases of skeletal muscle, hormone-sensitive lipase
(HSL) and alkaline lipoprotein lipase (LPL), with functional elements of lipid
metabolism (Fig. 4B). For
instance, HSL mRNA was significantly correlated with the volume density of
intramyocellular triglycerides and mitochondria, determined by electron
microscopy. HSL is known to reside at the periphery of triglyceride droplets
and liberates the entrapped triglycerides for mitochondrial oxidation (for
reviews, see Schmitt et al.,
2003; Donsmark et al.,
2004). The findings now imply a relationship between the flux of
fatty acids liberated from intramyocellular lipids (IMCL) on the one hand and
expression of the transcript encoding HSL on the other. Similarly, the
transcript level of the LPL was found to correlate with the absolute rate of
repletion of intramuscular triglyceride stores after exhaustive exercise
(Schmitt et al., 2003). LPL
hydrolyses fatty acids from lipoproteins and chylomicrons in the vasculature.
The molecular information implies that endurance training does improve
mitochondrial respiration along with an increase in the capacity to import
blood-borne fatty acids. The match of expressional adjustments in sequential
steps of the oxidative pathway in recruited muscle groups is interpreted to
reflect the local level of coordination, which contributes to the systemic
improvements of the oxygen pathway with endurance training
(Weibel et al., 1991).
Expressional mechanisms underlying symmorphosis
The correspondence of gene expression changes with functional adjustments
of the oxidative pathway after endurance training signals a distinct molecular
circuitry in skeletal muscle that underlies improved fatigue resistance. This
argument is supported by observations on an important correlation of the
transcript levels for HSL, COX1 and fatty acid binding protein of the heart
(H-FABP) in tibialis anterior muscle of untrained and endurance-trained
subjects (Schmitt et al.,
2003). This relationship calls for a specific mechanism capable of
coordinating adjustments in gene expression dependent on muscle recruitment.
The correspondence between two master transcriptional regulators of lipid
metabolism is striking, i.e. the peroxisome proliferator-activated receptors
and 
(PPAR and ), with HSL and LPL mRNA levels.
The PPARs are nuclear receptors that control transcription of a battery of
genes involved in fatty acid catabolism
(Smith, 2002). Free fatty
acids act as the main physiological substrates for the activation of PPARs and
the downstream activation of gene expression. In this regard, the relationship
between mitochondrial gene transcript number and the RNA concentration of
major regulators of mitochondrial biogenesis is also striking. For instance,
the mitochondrial transcription factor (Tfam) and peroxisome proliferator
coactivator-1 (PGC-1), known to lie up- and downstream of PPAR
action (reviewed in Fluck and Hoppeler,
2003), are significantly correlated with COX1 and COX4 mRNA
(Zoll et al., 2006). These
inter-gene relationships indicate a major role of the PPAR-pathway in the
control of mitochondrial phenotype by exercise. These steady-state adaptations
of the PPAR-system relate to the increased flux of fatty acids in muscle
tissue with a sustained increase in locomotion in man
(van Loon et al., 2001).
Consequently, the PPAR-system is seen to represent a major pathway that
underlies sensing and integration of exercise stimuli into modifications of
the oxidative pathway. This metabolically driven circuitry provides a
rationale for the symmorphotic adjustment in skeletal muscle with endurance
training and the suspected alteration in mitochondrial turnover
(Weibel et al., 1991;
Connor et al., 2000).
The muscular gene response and the repetition effect
By definition, training-induced muscle adjustments are the consequence of
repetition of single-exercise stimuli. Adaptations of muscle tissue to
increased contractile activity are proposed to be confined to the recovery
phase from each fatiguing bout of exercise
(Fluck, 2004;
Pilegaard et al., 2000). This
would allow an overshoot of cellular adaptations that support the accumulation
of incremental remodeling responses after each session, and with repetition of
the single-exercise stimuli this would support the enhanced endurance
performance (Fig. 5). The
extent to which gene expression processes underlie the continued build-up of
muscle structure and performance with each bout of exercise remains to be
explored.
|
To that end we hypothesized that a systematic exploration of changes in
mRNA levels would reveal the molecular strategies underlying muscle
plasticity. We employed microarray technology to test whether RNA adaptations
in the recovery phase contribute to exercise-induced build-up of muscle
tissue. This novel technology allows the parallel assessment of adjustments in
the levels of hundreds to thousands of transcripts. Nylon filters holding 222
cDNA probes for muscle-relevant factors were custom-designed for the detection
of reverse-transcribed RNAs after different recovery times from exercise
(Fluck et al., 2005a).
Exploration of the muscular adjustments revealed a general trend for a
transient upregulation 8 h after one bout of ergometer exercise
(Fig. 6)
(Schmutz et al., 2006). This
main response to 30 min of bicycling concerned gene families implicated in the
oxidative pathway. Multiple factors involved in the extracellular and
myocellular mobilization of fatty acids as well as mitochondrial beta
oxidation and the electron transport chain were affected. The acute adjustment
of the muscle transcriptome related to the oxidative pathway to 6 weeks of
training was found to recapitulate the known elevation with years of endurance
training (Fig. 3)
(Fluck and Hoppeler, 2003). The
results support the concept that microadaptations in expression after each
exercise bout instruct the structural–functional adjustments of
oxidative muscle metabolism to each exercise bout which accumulate with
repetition of exercise stimuli (Fig.
5).
|
Conversely, when typical muscle adjustments had been established after 6
weeks of endurance training this transcript response was specifically
modified. In particular, the acute induction of most transcripts to a matched
single exercise bout was blunted (not shown)
(Schmutz et al., 2006), which
can be explained by the increased steady-state mRNA levels and relates to the
reduced adaptive potential in trained individuals
(Saltin et al., 1977). These
observations reveal that a multi-faceted and coordinated expression program
underlies the specific muscular adjustments with the repeated impact of
exercise with training and relates to the sensitivity of response.
Hypoxia as a stimulus of the exercise response
In the context of the stimuli that instruct muscle plasticity, local
hypoxia has been postulated to constitute a main signal for muscular
adjustments to endurance exercise
(Hoppeler and Vogt, 2001),
given that there is a dramatic drop in muscle oxygen tension with the onset of
exercise (Richardson et al.,
1995; Richardson et al.,
2001). Similarly, ambient hypoxia reduces muscular oxygen levels
and is known to amplify the exercise-induced local muscle hypoxia
(Richardson et al., 1995;
Hoppeler et al., 2003). This
relates to the long-held theory of promotion of respiratory adjustments in
chronic hypoxia and the hypoxia-induced shift away from the oxidative
metabolisation of fatty acids towards increased utilization of carbohydrates
via the glycolytic pathway
(Reynafarje, 1962;
Hoppeler et al., 2003). We
therefore speculated that the addition of a defined normobaric hypoxic stress
to the stimulus of a 30 min ergometer-bout would shift the acute muscular
transcriptome response towards reduced level adjustments of transcripts
related to fatty acid metabolism. This assumption was tested in vastus
lateralis muscle of untrained subjects, and a blunting of the exercise-induced
transcript level response for factors of fatty acid transport in the recovery
phase after exercise at simulated altitude was seen
(Fig. 6B) (S. Schmutz,
unpublished observations). Similarly, the transcript expression of
mitochondrial respiratory factors was blunted during recovery from bicycling
in hypoxia. The differentiation of the acute molecular response to exercise in
untrained subjects by hypoxia highlights the physiological role of muscular
oxygen tension for the adjustments in striated muscle. The blunting of the
ATP-dependent mRNA response in untrained subjects probably relates to a
sizable drop in free energy levels in recruited muscle with the extra muscle
deoxygenation due to the hypoxic co-stimulus
(Kammermeier, 1987). The
appreciation of the hypoxia-specific modulation of human muscle's response to
exercise and the functional consequences for muscle remodeling invite further
exploration.
|
). The use
of inbred rodent models also has obvious advantages as it permits control over
experimental variables, reducing noise and variability and allowing
maximization of the physiological input that drives muscle plasticity (for a
review, see Wittwer et al.,
2004). We applied this tool towards elucidation of the role of the
alpha subunit of the hypoxia-inducible factor 1 (HIF-1) in response to
a reduction in ambient oxygen concentration. This factor acts as a regulatory
switch for hypoxia sensing in various cellular systems
(Semenza, 2000). In normoxia,
HIF-1 is rapidly tagged for degradation. Conversely, it is stabilized
in an organ-specific manner in hypoxia, permitting its association with the
HIF-1ß subunit to form the DNA-binding HIF-1 complex
(Pisani and Dechesne, 2005;
Stroka et al., 2001;
Yu et al., 1998). This
heterodimer initiates the transcription of various hypoxia-responsive genes of
metabolic processes that would be advantageous under the constraint of reduced
oxygen, such as capillary growth and glycolysis (for a review, see
Hoppeler et al., 2003).
The specific experimental set-up to elucidate the role of HIF-1 in
the muscular hypoxia response employed HIF-1 heterozygous-deficient
mice exposed to hypoxic vs normoxic air
(Fig. 7). Mice with one
HIF-1 allele ablated (HIF-1–/+) demonstrated a 30% lower
level of HIF-1 mRNA in the anti-gravitational soleus muscle under study
than control mice (Däpp et al.,
2006). Such a partial HIF-1 deficiency has been shown
before to interfere negatively with multiple systemic responses to hypoxia
(Yu et al., 1999). To test
this assumption, differences in hypoxia-induced adjustments in transcript
levels in soleus muscle under spontaneous cage activity were compared between
wild-type and HIF-1 heterozygous-deficient mice. Subsequently,
genotype-dependent differences of the effect of a 24 h exposure to hypoxia
were analyzed for major patterns using cluster analysis. This
multi-correlation algorithm identified that the expressional response of
muscle to hypoxia was distinct between the two genotypes
(Fig. 7A). Detailed inspection
of the indicated differences using probability testing demonstrated major
shifts in hypoxia-induced adjustments in expression related to carbohydrate
metabolism with a reduction of the HIF-1 mRNA level. In contrast, a
general level of reduction of transcripts related to fatty acid metabolism was
noted in hypoxia and reversed in the HIF-1 heterozygous-deficient mice
(Fig. 7C). Conversely,
hypoxia-induced mRNA levels of glycolytic factors were blunted in the mice
with reduced HIF-1 levels (Fig.
7B). As local hypoxia is a suspected consequence of ambient oxygen
concentration, the latter finding underscores the suspected role of hypoxia as
a major regulator of the muscle phenotype. Meanwhile the results also
highlight the importance of HIF-1 in the opposing regulation of
carbohydrate- and fat-metabolizing processes in muscle.
|
).
Interaction of these signaling events must be considered in order to explain
the complex physiological outcome of endurance exercise when combined with
co-stimuli such as hypoxia.
Conclusions
Taking all the above findings together, we infer that a complex gene
response reflects the specificity of the muscular adaptation to different
types of exercise. Co-regulation appears to exist across the oxidative
pathway, chromosomes and genomes. The apparent correlation within gene
families and structure–function relationships reveals that a distinct
molecular circuitry underlies symmorphosis of the pathway of oxygen,
suggesting the involvement of master switches in the coordination of the local
training response. The members of these pathways that integrate the
homeostatic perturbations in exercised muscle tissue into specific remodeling
of muscle organelles begin to be identified. The well-described phenomenology
of skeletal muscle plasticity and the unique features of this tissue behavior
such as specificity, reversibility, desensitization and accessibility, put
muscle into a unique position for future studies on the biological principles
underlying cell plasticity in vivo.
List of abbreviations
,ß,ß
Acknowledgments
The financial support of the Swiss National Science Foundation, the encouragement of Hans Hoppeler and the experimental support of Prof. Max Gassmann, Dr Christoph Däpp and Dr Silvia Schmutz are greatly acknowledged.
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P<0.10. For enzymes, see
List of abbreviations.
RNA),
which leads via translation to a microadaptation of the encoded
protein and related structure. This relays to the gradual accumulation
(
