Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.

Abstract

Skeletal muscle is essential for movement, respiration, and metabolism, with mTORC1 acting as a key regulator of protein synthesis and degradation. In aging muscle, mTORC1 becomes overactivated, contributing to sarcopenia, though the mechanisms remain unclear. Here, we identify DEAF1, a FOXO-regulated transcription factor, as a key upstream driver of mTORC1 in aged muscle. Elevated <i>Deaf1</i> expression increases <i>mTOR</i> transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence. Remarkably, exercise suppresses <i>Deaf1</i> expression via FOXO activation, restoring mTORC1 balance and alleviating muscle aging. Conversely, FOXO inhibition or <i>Deaf1</i> overexpression blocks exercise benefits on muscle health. These findings highlight DEAF1 as a critical link between FOXO and mTORC1 and suggest that targeting the FOXO-DEAF1-mTORC1 axis may offer therapeutic potential to preserve muscle function during aging.