Nature metabolismDec 3, 2025

Cell cleanup process supports muscle stem cell repair but decreases with age

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Chaperone-mediated autophagy appears to support muscle stem cell proliferation and regenerative capacity, while its decline contributes to aging-related impairment.

Evidence

This experimental study used genetic CMA loss, comparative proteomics, CMA reactivation, and glycolysis enhancement in young and aged murine and human muscle stem cells.

Caveat

The regenerative rescue evidence comes from muscle stem cell and mouse-focused experiments, so clinical effects in older humans are not established.

Simplified

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.