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Skeletal muscle is a vital metabolic organ that regulates systemic energy homeostasis by coordinating glucose uptake, fatty acid oxidation, and amino acid metabolism. Its remarkable capacity for dynamic adaptation, termed metabolic flexibility, underpins physical performance and protects against metabolic diseases such as obesity, type 2 diabetes, and sarcopenia. This review provides an integrative synthesis of the molecular and signaling networks that orchestrate skeletal muscle metabolism, focusing on key regulators including insulin, AMPK, mTOR, and PGC-1α. We also examine how disruptions in these pathways lead to mitochondrial dysfunction, lipid dysregulation, and muscle wasting. We explore the therapeutic landscape across pharmacological, exercise-based, and nutritional interventions, emphasizing mitochondrial-targeted strategies and myokine-mediated communication as emerging modalities for restoring metabolic resilience. Additionally, we emphasize the growing importance of multi-omics technologies and inter-tissue communication in improving mechanistic understanding and advancing precision medicine. This review integrates mechanistic, translational, and clinical perspectives to underscore the importance of a systems-level approach to skeletal muscle metabolism. This approach is essential for developing targeted, multidimensional therapies aimed at enhancing metabolic health and extending healthspan.
Lin et al. (Sat,) studied this question.