Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging

Choy, Sze Mun, Goh, Kah Yong, Lee, Wen Xing, Jiang, Weiyi, Gou, Qian, Gopal Krishnan, Priya D, Ong, Shi Chee, Chua, Kenon, Harmston, Nathan and Tang, Hong-Wen 2025. Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging. Proceedings of the National Academy of Sciences 122 (48) , e2508893122. 10.1073/pnas.2508893122

PDF - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (13MB)

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 Deaf1 expression increases mTOR transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence. Remarkably, exercise suppresses Deaf1 expression via FOXO activation, restoring mTORC1 balance and alleviating muscle aging. Conversely, FOXO inhibition or Deaf1 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Publisher:	National Academy of Sciences
ISSN:	1091-6490
Date of First Compliant Deposit:	26 November 2025
Date of Acceptance:	20 October 2025
Last Modified:	27 Nov 2025 09:47
URI:	https://orca.cardiff.ac.uk/id/eprint/182687

Actions (repository staff only)

Edit Item