Cellular Senescence in Skeletal Muscle: Molecular Mechanisms, Physiological Consequences, and Therapeutic Opportunities.

Cellular senescence is a stress-responsive cell fate characterized by stable growth arrest and acquisition of a proinflammatory senescence-associated secretory phenotype. Senescent cells accumulate with advancing age and contribute to dysfunction and disease across multiple organ systems. In skeletal muscle (SkM), emerging evidence indicates that senescence arises across diverse cell populations that collectively reshape the SkM niche. Through the SASP and altered intercellular signaling, senescent cells promote chronic inflammation, fibrosis, impaired regeneration, and metabolic dysfunction that contribute to SkM loss, SkM weakness, functional decline, and frailty. This review synthesizes current knowledge of the molecular drivers, hallmarks, and cellular origins of senescence within SkM and highlights the physiological consequences that extend from the cellular to the organismal level. We also discuss emerging senotherapeutic strategies that hold promise for optimizing SkM health and function with aging and disease.