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Regulation of skeletal muscle cell plasticity in health and disease

Skeletal muscle has an enormous capacity to adapt to external stimuli including physical activity, oxygen, temperature, nutrient availability and composition. Inadequate muscle function is linked to an increased risk for many chronic diseases such as obesity, type 2 diabetes, cardiovascular disorders, osteoporosis, neurodegenerative events, mood disorders, age-related muscle wasting, and certain cancers. Inversely, regular exercise is an excellent prevention and therapeutic intervention for many of these pathologies and improves life quality and expectancy.

Skeletal muscle cell plasticity in exercise is a complex process: even a single endurance exercise bout alters the transcription of more than 900 genes in muscle. Chronic exercise leads to a metabolic and myofibrillar remodeling, increase in tissue vascularization, adaptation of the neuromuscular junction, a shift in the balance between protein degradation and biosynthesis rates, elevated heme biosynthesis, improved reactive oxygen species detoxification and a resetting of the peripheral circadian clock. Due to this complexity, it is not surprising that our knowledge about the molecular mechanisms that underlie muscle cell plasticity remains rudimentary.

The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is one of the key factors in muscle adaptation to exercise. Muscle activity induces PGC-1α gene expression and promotes post-translational modifications of the PGC-1α protein. In turn, PGC-1α regulates the adaptations of muscle to endurance training. Accordingly, ectopic expression of PGC-1α in muscle is sufficient to induce a trained phenotype whereas mice with a genetic ablation of the PGC-1α gene in muscle have an impaired endurance capacity.

Our group is studying the mechanisms that control muscle cell plasticity and their physiological consequences. We try to integrate molecular biology, work in muscle cells in culture and observations on mice with different activity levels to obtain a comprehensive picture of the adaptations in the active and the inactive muscle.

Regulation and coordination of metabolic pathways
Endurance exercise is a strong promoter of mitochondrial biogenesis and oxidative metabolism of lipids. At the same time, skeletal muscle of endurance athletes exhibits increased storage of intramyocellular lipids, similar to what is observed in muscle of type 2 diabetic patients (the “athlete’s paradox”). Furthermore, the boost in mitochondrial function potentially augments the generation in harmful side-products, e.g. incomplete fatty acid oxidation products or reactive oxygen species. However, neither the lipid accumulation nor the oxidative metabolism in the exercised muscle exert detrimental effects, in stark contrast to the pathologies that develop under seemingly similar conditions in type 2 diabetes and other muscle-associated diseases. We study the coordination of anabolic and catabolic pathways in order to pinpoint the differences in substrate fluxes in the healthy and the diseased muscle.

Molecular changes in muscle atrophy and dystrophies
Muscle disuse, induced by a Western life-style or caused by diseases, leads to fiber atrophy, reduced muscle functionality and is ultimately fatal in certain inherited and sporadic muscular dystrophies. Little is known about the etiology of most of these diseases and as a result, no efficacious therapy exists for these devastating disorders. However, the induction of a trained phenotype ameliorates many of the symptoms of muscle wasting and thereby improves muscle function. For example, we have shown that using a genetic model for endurance training, PGC-1α muscle-specific transgenic mice, helps to ameliorate disuse-induced muscle fiber atrophy and Duchenne muscular dystrophy. Other groups have demonstrated that ectopically expressed PGC-1α also improves a mitochondrial myopathy, blunts muscle damage by the statin drugs and reduces sarcopenia, muscle wasting in aging in the respective animal models. We are currently studying how PGC-1α mediates this broad spectrum, health-beneficial effect on muscle and how this could be exploited therapeutically.

Integration of signaling pathways and spatiotemporal control of gene expression
In exercise, PGC-1α transcription, protein levels and activity are modulated by different signaling pathways. While all of the major signaling pathways in the trained muscle converge on PGC-1α (figure part A), the consequences, the integration and the temporal coordination of these signals are not clear. Upon activation, PGC-1α controls the transcription of many different gene families in muscle to promote a trained phenotype. However, the specificity of gene regulation by PGC-1α varies according to the cellular context (figure part B). For example, the regulation of postsynaptic neuromuscular junction genes by PGC-1α is spatially restricted to subsynaptic nuclei in the muscle fiber.

Important Partners
Johan Auwerx (Ecole Polytechnique Federale de Lausanne, CH); Urs Boutellier (Eidgenossische Technische Hochschule Zurich, CH); Daniel Eberli (Universitatsspital Zurich, CH); Hans Hoppeler (Universitat Bern, CH); Markus A. Ruegg (Biozentrum, Basel, CH); Bruce M. Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, US); Erik van Nimwegen (Biozentrum, Basel, CH); Mihaela Zavolan (Biozentrum, Basel, CH); Francesco Zorzato (Universitatsspital Basel, CH)

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