Mechanisms of Impaired Skeletal Muscle Regeneration and Therapeutic Approaches in Aging and Chronic Disease

Skeletal muscle regeneration is essential for recovery after injury and for maintaining physical and metabolic function. This capacity declines with aging and is often impaired in chronic diseases, limiting effective repair. This review summarizes the main mechanisms that regulate muscle repair, with a focus on satellite cell activity and its interaction with inflammatory, metabolic, vascular, and fibrotic signals at the molecular and cellular level. We discuss how these processes are disrupted in aging, Duchenne muscular dystrophy, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, and cancer cachexia, leading to delayed repair, reduced myogenic differentiation, and fibrosis. We also review current and emerging strategies to improve muscle regeneration, including exercise, bioactive molecules, physical stimulation, gene-based approaches, engineered biomaterials, and cell or cell-derived therapies. Across these conditions, chronic inflammation, metabolic dysfunction, and fibrotic remodeling appear to be common barriers to effective regeneration. Multi-target therapeutic approaches may offer advantages over single-pathway interventions, although clinical evidence is still limited; initial preclinical results, however, are promising.