Butcher, C. | Search bioRxiv

bioRxiv2026

The Muscle Tissue Environment Limits Muscle Stem Cells in Aged Mice

Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes. Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.

cell biology↗

bioRxiv2025

AMPK alters proteasome phosphorylation status and prevents persistent proteasome condensates

Proteasomes are large multiprotein complexes required for selective intracellular protein degradation, regulating numerous cellular processes and maintaining protein homeostasis and organismal health. In the budding yeast Saccharomyces cerevisiae grown under different glucose conditions, proteasomes undergo dynamic phase transitions between free and condensate states concomitant with nucleocytoplasmic translocation. Low glucose-induced cytoplasmic proteasome condensates are usually reversible but become persistent in the absence of AMP-activated protein kinase (AMPK). AMPK is important for proteasome condensate dissolution and proteasome nuclear reimport upon glucose refeeding of quiescent cells. Here we found that AMPK activities and the AMPK signaling pathway affect proteasome subunit phosphorylation, which correlates with the solubility and reversibility of proteasome condensates. Nuclear and cytoplasmic AMPK functions redundantly in proteasome condensate dissolution. AMPK interacts with the proteasome regulatory particle in an AMPK activity-independent manner. At least 50 kinases and phosphatases have been found to associate with the AMPK complex. Therefore, the prevention of persistent proteasome condensate formation by AMPK likely results from regulating the antagonistic effects of downstream kinases and phosphatases on proteasome phosphorylation. A mechanistic understanding of the downstream effector proteins of AMPK that directly regulate proteasome subunit phosphorylation will provide insights into how proteasome phosphorylation is linked to proteasome condensate regulation. Article summaryProteasomes undergo dynamic nucleocytoplasmic translocation and phase transitions in response to glucose starvation. AMP-activated protein kinase (AMPK) is important for cytoplasmic proteasome condensate dissolution and proteasome nuclear reentry in budding yeast cells upon glucose refeeding of quiescent cells. This study demonstrates that AMPK interacts with proteasomes, and the AMPK pathway regulates proteasome phosphorylation status and condensate solubility during reversible proteasome condensate formation. AMPK and the PP1 phosphatase dynamically regulate phosphorylation of multiple proteasome subunits. Therefore, the regulation of proteasome phosphorylation by AMPK is likely to be central to proteasome biomolecular condensate formation and dissolution.

cell biology↗