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

Area of Science:

• Molecular biology
• Gerontology
• Muscle physiology

Background:

• Skeletal muscle's role in movement, respiration, and metabolism is crucial.
• The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of muscle protein synthesis and degradation.
• Overactivated mTORC1 in aging muscle contributes to sarcopenia, but upstream mechanisms are not fully understood.

Purpose of the Study:

• To identify upstream regulators of mTORC1 overactivation in aged skeletal muscle.
• To elucidate the role of DEAF1 in age-related muscle dysfunction.
• To investigate the interplay between FOXO, DEAF1, and mTORC1 in muscle aging and exercise response.

Main Methods:

• Analysis of gene expression in aged muscle models.
• Investigating the transcriptional regulation of mTOR by DEAF1.
• Utilizing FOXO inhibition and DEAF1 overexpression models to assess functional impacts.
• Examining the effects of exercise interventions on the FOXO-DEAF1-mTORC1 axis.

Main Results:

• DEAF1 is identified as a FOXO-regulated transcription factor that drives mTORC1 overactivation in aged muscle.
• Elevated Deaf1 expression increases mTOR transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence.
• Exercise suppresses Deaf1 expression through FOXO activation, which restores mTORC1 balance and alleviates muscle aging phenotypes.
• FOXO inhibition or Deaf1 overexpression negates the beneficial effects of exercise on muscle health.

Conclusions:

• DEAF1 acts as a critical link between FOXO signaling and mTORC1 activity in skeletal muscle aging.
• Targeting the FOXO-DEAF1-mTORC1 axis presents a potential therapeutic strategy for preserving muscle function in aging.
• Understanding this pathway could lead to novel interventions for sarcopenia and other age-related muscle degenerative conditions.