DEAF1 - a transcriptional brake on muscle autophagy

Macroautophagy/autophagy protects muscle from proteotoxic stress and maintains tissue homeostasis, yet skeletal muscle relies on it more than most organs. Adult fibers endure constant mechanical strain and require continuous turnover of long-lived proteins, while muscle stem cells (MuSCs) depend on autophagy to remain quiescent, activate after injury, and regenerate effectively. How autophagy is transcriptionally regulated in muscle has been unclear. We identified DEAF1 as a transcriptional brake on autophagy. In MuSCs, DEAF1 controls activation and regeneration and becomes aberrantly elevated with age, promoting protein aggregate formation and cell death. In muscle fibers, DEAF1 is chronically induced during aging, suppressing autophagy and driving functional decline. Exercise reverses DEAF1 induction, restoring autophagy and muscle function. These findings reveal DEAF1 as a key regulator linking autophagy to regeneration and aging, highlighting a therapeutically tractable axis for preserving muscle health.