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Coactivator-controlled transcriptional networks regulating skeletal muscle cell plasticity

Final Report Summary - MUSCLE-NET (Coactivator-controlled transcriptional networks regulating skeletal muscle cell plasticity)

Our well-being and health relies to a large extent on adequate function of skeletal muscle. For example, a sedentary life-style is a strong risk factor for many diseases, including metabolic pathologies such as type 2 diabetes or obesity, cardiovascular disorders, certain types of cancer, age-related muscle wasting, depression, or neurodegeneration in dementia, Alzheimers or Parkinsons. Inversely, clear epidemiological and clinical evidence exists for a strong therapeutic effect of exercise training in the prevention and treatment of many diseases. Muscle cells exhibit an enormous capacity to undergo plastic changes, which, e.g. in the context of exercise, confer local and systemic health benefits. Curiously, despite this clear implication in health, the molecular pathways that control skeletal muscle plasticity in health and disease are still poorly understood. The support that was provided by this ERC Consolidator grant enabled the study of these pathways, in particular of the regulators that control gene expression in skeletal muscle cells in different physiological and pathological contexts. For example, we delineated the temporal changes that occur in young and old skeletal muscle. These changes were then compared to those elicited by exercise, and thereby, we studied how age-related aspects of skeletal muscle biology, e.g. the reduction in strength or endurance, can be mitigated or even reversed by alterations of specific molecular pathways. More broadly, the results obtained within the framework of this ERC grant support have now greatly expanded our knowledge of the mechanistic underpinnings of skeletal muscle biology. Many of our studies were centered on a protein called PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha), a key regulatory nexus in endurance training-adaptation of skeletal muscle. By interrogating how PGC-1alpha is regulated, and how PGC-1alpha coordinates the broad adaptation of muscle, we now provide a clear mechanistic framework that can be leveraged in situations of muscle inactivity, e.g. that observed in muscular dystrophies or aging. Thus, of note, the results that were obtained are not only of interest for our basic understanding of muscle physiology, but have also helped to initiate collaborations with biotech companies to leverage some of the new knowledge to design novel approach for the treatment of sarcopenia, age-related muscle wasting.