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Molecular Mechanisms of Muscle Plasticity with Exercise

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The skeletal muscle phenotype is subject to considerable malleability depending on use. Low‐intensity endurance type exercise leads to qualitative changes of muscle tissue characterized mainly by an increase in structures supporting oxygen delivery and consumption. High‐load strength‐type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In low‐intensity exercise, stress‐induced signaling leads to transcriptional upregulation of a multitude of genes with Ca2+ signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several parallel signaling pathways converge on the transcriptional co‐activator PGC‐1α, perceived as being the coordinator of much of the transcriptional and posttranscriptional processes. High‐load training is dominated by a translational upregulation controlled by mTOR mainly influenced by an insulin/growth factor‐dependent signaling cascade as well as mechanical and nutritional cues. Exercise‐induced muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. Crucial nodes of strength and endurance exercise signaling networks are shared making these training modes interdependent. Robustness of exercise‐related signaling is the consequence of signaling being multiple parallel with feed‐back and feed‐forward control over single and multiple signaling levels. We currently have a good descriptive understanding of the molecular mechanisms controlling muscle phenotypic plasticity. We lack understanding of the precise interactions among partners of signaling networks and accordingly models to predict signaling outcome of entire networks. A major current challenge is to verify and apply available knowledge gained in model systems to predict human phenotypic plasticity. © 2011 American Physiological Society. Compr Physiol 1:1383‐1412, 2011.

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Figure 1. Figure 1.

Schematic outline of the muscular signal integration of physical exercise stimuli. The stimulation of muscle tissue by exercise bouts is integrated by complex signaling networks causing changes in protein quantity, activity, and localization by adjusting transcriptional and/or translational mechanisms.

Figure 2. Figure 2.

A simplified scheme summarizing some known signaling pathways/networks that are preferentially activated with endurance‐type training. Energy depletion and elevated calcium levels are the main stressors initiating mitochondrial biogenesis and slow fiber programs by increasing PGC‐1alpha transcription. Consult “Endurance Exercise Training” paragraph for details.

Figure 3. Figure 3.

A selection of stressors and subsequent signaling pathways and networks engaged with strength‐type training. The Akt‐mTOR pathway is thought to be the main integrator of mechanical stress and hormonal stimulation. Downstream activation of p70S6K, initation, and elongation factors leads to an increased mRNA translation. As a consequence of the gain in muscle mass, number of nuclei (proliferation of satellite cells) must be adjusted to maintain a constant myonuclear domain. Consult “Strength Training” paragraph for details.

Figure 4. Figure 4.

Simplified model of the molecular interference of endurance and strength training. AMPK (endurance) and mTOR (strength) activity are thought to be the main points of divergence with concurrent endurance and strength exercise training. Consult “Interactions Between Endurance and Strength Training” paragraph for details.

Figure 1.

Schematic outline of the muscular signal integration of physical exercise stimuli. The stimulation of muscle tissue by exercise bouts is integrated by complex signaling networks causing changes in protein quantity, activity, and localization by adjusting transcriptional and/or translational mechanisms.

Figure 2.

A simplified scheme summarizing some known signaling pathways/networks that are preferentially activated with endurance‐type training. Energy depletion and elevated calcium levels are the main stressors initiating mitochondrial biogenesis and slow fiber programs by increasing PGC‐1alpha transcription. Consult “Endurance Exercise Training” paragraph for details.

Figure 3.

A selection of stressors and subsequent signaling pathways and networks engaged with strength‐type training. The Akt‐mTOR pathway is thought to be the main integrator of mechanical stress and hormonal stimulation. Downstream activation of p70S6K, initation, and elongation factors leads to an increased mRNA translation. As a consequence of the gain in muscle mass, number of nuclei (proliferation of satellite cells) must be adjusted to maintain a constant myonuclear domain. Consult “Strength Training” paragraph for details.

Figure 4.

Simplified model of the molecular interference of endurance and strength training. AMPK (endurance) and mTOR (strength) activity are thought to be the main points of divergence with concurrent endurance and strength exercise training. Consult “Interactions Between Endurance and Strength Training” paragraph for details.

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Hans Hoppeler, Oliver Baum, Glenn Lurman, Matthias Mueller. Molecular Mechanisms of Muscle Plasticity with Exercise. Compr Physiol 2011, 1: 1383-1412. doi: 10.1002/cphy.c100042