Mechanistic interactions of diet, exercise, and pharmacotherapy in skeletal muscle metabolism: evidence and translational perspectives

Skeletal muscle plays a central role in whole-body energy homeostasis, metabolic flexibility, and insulin sensitivity, acting as a key integrator of nutritional, mechanical, and pharmacological signals. Although diet, exercise, and pharmacotherapy are often investigated as separate interventions, they converge on shared regulatory pathways in skeletal muscle, including nutrient sensing, mechanotransduction, mitochondrial quality control, inflammatory remodeling, and anabolic-catabolic balance. Through core signaling networks such as AMPK-mTOR, SIRT1/PGC-1α, and insulin/AKT pathways, these interventions may interact in additive, complementary, synergistic, or antagonistic manners depending on physiological status, disease context, baseline metabolic condition, and intervention timing. This Review critically integrates current evidence on how diet, exercise, and pharmacotherapy regulate skeletal muscle metabolism across aging, metabolic disease, and adaptive physiological states. We propose a muscle-centered integrative framework organized around five major regulatory domains: substrate utilization and metabolic flexibility, mitochondrial remodeling, protein turnover, inflammatory control, and regenerative capacity. Within this framework, we highlight how intervention responses are shaped by key biological and clinical modulators, including age, disease state, muscle fiber composition, training status, nutritional background, and baseline metabolic health. Importantly, we distinguish findings supported by human studies from those derived primarily from preclinical or mechanistic models, thereby emphasizing differences in translational reliability. Finally, we discuss current limitations in interpreting combined interventions and outline future directions for precision-oriented strategies that integrate nutrition, exercise, and pharmacotherapy to optimize skeletal muscle function and systemic metabolic health.