Polyamines and autophagy as a dynamic regulatory network in skeletal muscle regeneration and aging.

Abstract

Autophagy is a core cellular mechanism that preserves tissue homeostasis by removing damaged proteins and organelles. In skeletal muscle, proper regulation of autophagic flux is essential for maintaining metabolic and structural integrity, whereas its disruption contributes to muscle atrophy, metabolic dysfunction, and age-related functional decline. Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience, with beneficial effects on stress responses, metabolic regulation, and lifespan extension. Physical exercise likewise acts as a physiological inducer of autophagy, promoting muscle remodelling, mitochondrial quality control, and adaptive responses to stress. Within this framework, spermine oxidase (SMOX) has emerged as a relevant regulator of muscle homeostasis. SMOX expression is maintained in healthy muscle but declines in atrophic conditions. By converting spermine into spermidine, SMOX may help sustain autophagy-related pathways and support muscle mass under physiological conditions. This review explores the interplay between exercise, spermidine, and SMOX, highlighting autophagy as a unifying regulatory axis. We summarize current evidence on their individual and combined roles in preserving muscle function and discuss their potential relevance for promoting healthy muscle aging and counteracting sarcopenia.