Pgc-1α is an exercise-responsive regulator of myosteatosis in older individuals

SUMMARY Accumulated fat in skeletal muscle, common in sedentary older individuals, compromises skeletal muscle health and function. Mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy aging. Using a network paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study uncovered a novel molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for the fat accumulation. Specifically, gene set enrichment analyses (GSEA) with network propagation revealed Pgc1 α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity. Integrated in silico and in situ approaches to induce Pgc-1 α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAPs adipogenesis. These findings suggest that Pgc1 α is a master regulator by which physical activity regulates fat accumulation in aged skeletal muscle. GRAPHICAL ABSTRUCT