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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

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Functional, structural and molecular plasticity of mammalian skeletal muscle in response to exercise stimuli

Martin Flück

Unit for Functional Anatomy, Department of Anatomy, University of Berne, Baltzerstrasse 2, Switzerland

View larger version (27K): [in a new window]   Fig. 1. Concept of the integration of physiological stimuli in phenotypic responses. Homeostatic perturbations such as those induced by exercise in muscle are integrated via signaling pathways into alterations in gene transcription. The diffusible gene copies produced then provide the message for the instruction of muscle tissue remodeling via translation and assembly of the encoded proteins. Based upon this relationship it is hypothesized that the systematic exploration of differences in transcript levels relative to phenotypic adjustments arising from the impact of exercise will reveal the strategy underlying muscle plasticity.

View larger version (33K): [in a new window]   Fig. 2. Metabolic processes in muscle fibers. The main biochemical processes involved in energy generation in striated muscle involve the combustion of fatty acids and carbohydrates. Carbohydrates (orange) are imported via facilitative processes from the capillary supply lines to the myofibre, where they may be stored as intramuscular triglycerides or glycogen, respectively, for later combustion. Fatty acid metabolization (green box) is an obligatory aerobic process that takes place in mitochondria via beta-oxidation and the Krebs cycle. In contrast, the `metabolic conversion' of carbohydrates via glycolysis in the cytoplasm (orange box) is oxygen-independent and is not necessarily coupled to mitochondrial respiration. This may lead to the production of the anaerobic end-product lactate. The decomposition of organic backbones in mitochondria produces reduction equivalents (and CO2), the former of which drive the oxygen-dependent generation of ATP via coupling to respiratory chain. Boxed factors are the crucial proteins involved at successively aligned transport, storage and conversion steps of metabolic pathways in striated muscle and whose mRNA expression was investigated. Endothelial LPL is involved in transporting fatty acids (FA) from the vasculature through the interstitium into the myocellular compartment (Glatz and Storch, 2001; Jeukendrup, 2002). There H-FABP is believed to play a main role in the intramyocellular transport of free FA. HSL liberates free FA from IMCL for mitochondrial oxidation. CPT I is a key enzyme for the uptake of FA into the mitochondrial matrix. The Krebs cycle enzymes Fum and SDH and the constituents of the electron transport chain, NADH6, COX1 and COX4, are then responsible for oxygen-dependent ATP production during mitochondrial respiration. PFKM represents a main control step for entry of carbohydrates into the glycolytic pathway. For further explanation, see List of abbreviations.

View larger version (18K): [in a new window]   Fig. 3. Transcriptional basis of the tuning of oxidative capacity by endurance training. (A) Normalized maximal (VO2max) consumption, mitchondrial volume and mitochondrial RNA levels of various respiratory proteins in m. vastus lateralis of endurance runners vs untrained subjects. mRNA levels are relative to levels of 28S rRNA. (B) Differences in concentration of transcripts in tibialis anterior muscle between untrained and endurance-trained subjects relative to 18S rRNA. Values are means ± s.e.m. Black boxes denote those mRNAs being encoded by mitochondrial DNA. Trained subjects had been exposed to years of endurance training and competition. Significant differences between values from endurance-trained vs untrained subjects are indicated: *P<0.05; P<0.10. For enzymes, see List of abbreviations.

View larger version (40K): [in a new window]   Fig. 4. Symmorphosis at the RNA level. Transcript–structure correlations bring about significant functional relationships. These concern the coordination of gene expression between the nuclear and mitochondrial genomes and the match of lipase expression to rate and capacity of fatty acid metabolism. (A) Correlation of mitochondrial-encoded COX1 and nuclear-encoded COX4 mRNA levels with mitochondrial volume density per fiber, i.e. Vv(mt,f). (B) Micrograph showing an intramyocellular droplet of lipid (IMCL) being enveloped by a mitochondrion. The pathway involved in the oxidative combustion of IMCL-derived fatty acids (FA) in mitochondria is indicated by a green arrow. The suspected localization of HSL and the correlation coefficients (r) between HSL mRNA with volume density of intramuscular lipids, Vv(li,f), and volume density of mitochondria, Vv(mt,f), are given in black and white font, respectively.

View larger version (17K): [in a new window]   Fig. 5. Microadaptations of transcript expression relate to the training effect. Model of the increase in (mitochondrial) RNA and endurance performance with repetition of exercise. Each bout of exercise leads to an overshoot of transcript levels in the recovery phase from fatiguing exercise (RNA), which leads via translation to a microadaptation of the encoded protein and related structure. This relays to the gradual accumulation () of mitochondrial volume density and the improved oxidative capacity with repetition of endurance exercise. A match of transcriptional, structural and functional parameters is observed in recruited muscle groups between untrained and endurance-trained steady states. Black stippled and solid lines indicate the evolution of RNA levels and performance, respectively, during the training.

View larger version (25K): [in a new window]   Fig. 6. Time-course of the muscular exercise response in (A) normoxia and (B) hypoxia. Untrained male subjects exercised for 30 min at the aerobic threshold on a bicycle ergometer while breathing normoxic (21% O2) or hypoxic air (13% O2, N=6/group). Biopsies were harvested during the time-course of recovery from this single bout of exercise. Total RNA was isolated and subjected to expression profiling using custom-made microarrays (Fluck et al., 2005a; Schmutz et al., 2006). Transcript signals were related to the internal 28S rRNA reference and analyzed for statistical significance using a Friedman ANOVA. The significant changes of selected transcripts related to the oxidative pathway, such as fatty acid transport, beta oxidation and mitochondrial respiration, are shown in A and B. Significantly altered mRNA levels throughout the time-course of recovery are underlined. Unaffected transcript levels of the main cytoskeletal factors titin and desmin demonstrate the specificity of effect.

View larger version (32K): [in a new window]   Fig. 7. The muscular hypoxia-response is HIF-1 dependent. Spontaneously active HIF-1 heterozygous-deficient mice (HIF-1–/+) and wild-type mice (WT) were subjected to 24 h of normoxia (21% O2) or hypoxia (10.5% O2, N=6/group). M. solei were harvested from the four experimental groups and analyzed with custom-designed microarrays for expression of 222 muscle-relevant transcripts (Fluck et al., 2005a; Dapp et al., 2004). The hypoxia-to-normoxia signal ratio of 142 detected transcripts was assessed by descriptive cluster analysis (A) and probability testing (B,C) to identify genotype-dependent differences in the hypoxia response (Däpp et al., 2006). (A) Hierarchical cluster analysis visualizing the global pattern of hypoxia-induced expression changes for the different experiments. The correlations (r) of the transcript response in hypoxia are reflected by the line length in the dendrogram. Alterations of expression levels for each transcript and experiment are given in color coding (up, red; down, blue). The clustering was recalculated as described (Fluck et al., 2005b) for centered correlations from the data of (Däpp et al., 2006) using log-transformed and mean-centered data. Note: the hypoxia expression patterns group according to the respective genotype. Distinct clusters of HIF-1-dependent transcripts, which demonstrate co-regulated level changes upon hypoxia and whose response was `inverted' in HIF-1 deficient muscle, are boxed. (B,C) Mean and standard error of significant transcript level differences for factors involved in the successive steps of glycolysis (B) and fatty acid metabolism (C). Gene expression alterations in HIF-1–/+ mice are shown in pink. Note: the muscular transcript response of glycolytic and oxidative pathways in hypoxia is reversed in HIF-1-deficient mice.

View larger version (30K): [in a new window]   Fig. 8. Scheme visualizing the integration of the complex stimulus of exercise in recruited skeletal muscle. Different homeostatic perturbations, such as those related to metabolic flux, loading, hormonal and neuronal alterations, are converted by specific sensory molecules into the activation of signaling cascades. These ultimately control muscle fate via the regulation of gene expression. Distinct master switches evolve that relate to the main themes of the gene expressional response in striated muscle. These phenomena involve the cooperation of gene expressional regulation of metabolic pathways, the coordination between nuclear and mitochondrial genomes and the specificity of the muscular adaptation with respect to the `composition' of the respective exercise stimulus. Consequently, gene expression represents an important layer of control for the processing of physiological information towards a biological outcome.