Molecular Basis of Exercise-Induced Skeletal Muscle Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future Challenges

We provide an overview of groundbreaking studies that laid the foundation for our current understanding of exercise-induced mitochondrial biogenesis and its contribution to human skeletal muscle fitness. We highlight the mechanisms by which skeletal muscle responds to the acute perturbations in cellular energy homeostasis evoked by a single bout of endurance-based exercise and the adaptations resulting from the repeated demands of exercise training that ultimately promote mitochondrial biogenesis through hormetic feedback loops. Despite intense research efforts to elucidate the cellular mechanisms underpinning mitochondrial biogenesis in skeletal muscle, translating this basic knowledge into improved metabolic health at the population level remains a future challenge.