Fine-Tuning Autophagy in Skeletal Muscle: From Homeostasis to Muscle Wasting Disorders.

Skeletal muscle homeostasis and regenerative capacity depend on efficient protein turnover, organelle quality control, and metabolic adaptation. Disruption of these processes contributes to muscle atrophy and functional decline during aging and various pathological conditions. Autophagy, a lysosome-dependent degradative pathway, maintains muscle integrity by clearing damaged proteins and organelles, preserving mitochondrial quality, and supporting muscle stem cell (MuSC) function. Both insufficient and excessive autophagy are detrimental: reduced flux impairs proteostasis, mitochondrial function, and regeneration, whereas hyperactivation drives excessive protein degradation, mitochondrial loss, and muscle wasting under stress. This review discusses molecular mechanisms regulating autophagy in skeletal muscle, including nutrient- and energy-sensing pathways (AMPK and mTORC1), transcriptional control of autophagy and lysosomal genes, and mitochondrial modulators. Evidence from genetic models and disease contexts indicates that both insufficient and excessive autophagy are associated with muscle degeneration, highlighting the need for balanced autophagic control rather than simple activation or inhibition. Together, these observations support a conceptual framework in which skeletal muscle health depends on maintaining autophagic activity within a context-dependent functional range, although this range is not yet quantitatively defined. This framework provides a useful basis for considering therapeutic strategies targeting muscle wasting.