"Regular physical activity is linked to improved health and increased life expectancy. Inversely, a sedentary life-style is a strong and independent risk factor for many chronic diseases, including obesity, type 2 diabetes or cardiovascular disorders, as well as certain types of cancer or neurodegeneration. Interestingly however, the molecular mechanisms that mediate the health beneficial effects of exercise, or those that trigger the pathological changes in diseases, are largely unknown.
The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is one of the major regulatory hubs of muscle adaptation to endurance training. Accordingly, elevated expression of PGC-1α in muscle is sufficient to induce a trained phenotype in mice. Inversely, mice lacking a functional PGC-1α gene in skeletal muscle exhibit many signs of pathological inactivity. Finally, PGC-1α expression is dysregulated in pathological contexts in human muscle, including type 2 diabetes and aging. Therefore, the study of the regulation and function of PGC-1α in muscle has the potential to yield important insights into the molecular mechanisms that control muscle health.
Unfortunately, the characterization of PGC-1α is drastically hampered by the high complexity of the transcriptional network controlled by this coactivator protein, which binds to many different transcription factor binding partners in a cell context-specific manner. Moreover, PGC-1α seems to directly couple transcription to RNA processing, thereby further complicating the analysis of PGC-1α-controlled biological programs. Our proposal combines novel innovative experimental and biocomputational approaches with the physiological study of healthy and diseased muscle cells ex vivo and in different animal models targeted on PGC-1α. Together, our findings will reveal novel insights on muscle function and may substantially shape the development of exercise mimetic-based therapies."
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