The interaction between exercise and autophagic flux in neurodegenerative muscleloss

Neurodegenerative diseases are increasingly recognized as systemic disorders that extend beyond the central nervous system and profoundly affect skeletal muscle. Muscle weakness and atrophy in these conditions are driven not only by denervation but also by mitochondrial dysfunction, chronic inflammation, and impaired proteostasis. Among the mechanisms underlying muscle deterioration, autophagy has emerged as a critical regulator of cellular quality control. Balanced autophagic flux is essential for the removal of damaged proteins and dysfunctional mitochondria, thereby preserving metabolic homeostasis and neuromuscular junction stability. Conversely, dysregulated autophagy contributes to proteotoxic stress and accelerates muscle degeneration in neurodegenerative disorders. Exercise is a potent physiological stimulus capable of modulating autophagy in skeletal muscle. Preclinical models and emerging clinical evidence indicate that appropriately prescribed exercise can restore impaired autophagic flux, enhance mitochondrial quality control, and improve muscle function in neurodegenerative and aging-related muscle loss. However, the effects of exercise are context- and intensity-dependent, underscoring the need for individualized therapeutic strategies. This review synthesizes current evidence on the interaction between exercise and autophagic regulation in neurodegenerative muscle loss. Exercise as a therapeutic strategy is supported by well-defined molecular and cellular mechanisms, including the regulation of autophagy and mitochondrial quality control.