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Chaperone-mediated autophagy sustains muscle stem cell regenerative function

ABSTRACT: Proteostasis supports stemness and its loss correlates with the functional decline of diverse stem cell types. Here we identify that chaperone-mediated autophagy (CMA), a selective autophagy pathway, is necessary for the regenerative capacity of muscle stem cells (MuSCs) throughout life. We show that CMA is active in MuSCs, while genetic loss of CMA in MuSCs or failure of CMA in normally aged cells causes a proliferative impairment, resulting in defective skeletal muscle regeneration. Reactivation of CMA in old MuSCs boosts their proliferative capacity and improves their regenerative ability. Using comparative proteomics to identify CMA substrates, we uncovered actin cytoskeleton and glycolytic metabolism as key processes altered in aged mice and human MuSCs. Our findings reveal CMA to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in old age.

ORGANISM(S): Mus musculus

PROVIDER: GSE286877 | GEO | 2025/10/15

REPOSITORIES: GEO

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Chaperone-mediated autophagy sustains muscle stem cell regenerative function

Project description:Proteostasis supports stemness and its loss correlates with the functional decline of diverse stem cell types. Here we identify that chaperone-mediated autophagy (CMA), a selective autophagy pathway, is necessary for the regenerative capacity of muscle stem cells (MuSCs) throughout life. We show that CMA is active in MuSCs, while genetic loss of CMA in MuSCs or failure of CMA in normally aged cells causes a proliferative impairment, resulting in defective skeletal muscle regeneration. Reactivation of CMA in old MuSCs boosts their proliferative capacity and improves their regenerative ability. Using comparative proteomics to identify CMA substrates, we uncovered actin cytoskeleton and glycolytic metabolism as key processes altered in aged mice and human MuSCs. Our findings reveal CMA to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in old age.

2025-10-17 | PXD059966 | Pride

Proteomic analysis of the role of chaperone-mediated autophagy (CMA) in muscle stem cells (MuSCs) regenerative functions

Project description:Proteomic analysis of the role of chaperone-mediated autophagy (CMA) in muscle stem cells (MuSCs) regenerative functions. Here, cultured WT (Lamp2a WT) and CMA-deficient (Lamp2a Pax7CreER) MuSCs. 6 replicates per group, and 300.000 cells per sample.

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Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration

Project description:In aging, skeletal muscle strength and regenerative capacity declines due, in part, to functional impairment of muscle stem cells MuSCs, yet the underlying mechanisms remain elusive. Here we capitalize on mass-cytometry to identify high CD47 expression as a hallmark of dysfunctional MuSCs CD47hi with impaired regenerative capacity that predominate with aging. The prevalent CD47 hi MuSC subset suppresses the residual functional CD47 lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. We uncover that elevated CD47 levels on aged MuSCs result from increased U1 snRNA expression, which disrupts alternative polyadenylation. The deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blocking of CD47 alternative polyadenylation or antibody blockade of CD47 signaling, leading to improved regeneration in aged mice, with therapeutic implications. Our findings highlight a previously unrecognized age-dependent alteration in CD47 levels and function in MuSCs, which underlies reduced muscle repair in aging.

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Deep proteome of aging skeletal muscles reveals Smoc2 as a modulator of satellite cell regenerative capacity

Project description:During aging, the number and functionality of muscle stem cells (MuSCs) decreases leading to impaired regeneration of aged skeletal muscle. In addition to intrinsic changes in aged MuSCs, extracellular matrix (ECM) proteins deriving from other cell types, e.g., fibrogenic-adipogenic progenitor cells (FAPs), contribute to the aging phenotype of MuSCs and impaired regeneration in the elderly. So far, no comprehensive analysis on how age-dependent changes in the whole skeletal muscle proteome affect MuSC function have been conducted. Here, we investigated age-dependent changes in the proteome of different skeletal muscle types by applying deep quantitative mass spectrometry. We identified 183 extracellular matrix proteins that show different abundances in skeletal muscles of old mice. By integrating single cell sequencing data, we reveal that transcripts of those ECM proteins are mainly expressed in FAPs, suggesting that FAPs are the main contributors to ECM remodelling during aging. We functionally investigated one of those ECM molecules, namely Smoc2, which is aberrantly expressed during aging. We show that Smoc2 levels are elevated during regeneration and that its accumulation in the aged MuSC niche causes impairment of MuSCs function through constant activation of integrin/MAPK signaling. In vivo, supplementation of exogenous Smoc2 hampers the regeneration of young muscles following serial injuries, leading to a phenotype reminiscent of regenerating aged skeletal muscle. Taken together, we provide a comprehensive resource of changes in the composition of the ECM of aged skeletal muscles, we pinpoint the cell types driving these changes, and we identify a new niche protein causing functional impairment of MuSCs thereby hampering the regeneration capacity of skeletal muscles.

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Deep proteome of aging skeletal muscles reveals Smoc2 as a modulator of satellite cell regenerative capacity

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Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling [CUT&Run]

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Project description:Muscle stem cells (MuSCs) are required for muscle regeneration. In resting muscles, MuSCs are kept in quiescence. After injury, MuSCs undergo rapid activation, proliferation and differentiation to repair damaged muscles. Age-associated impairments in stem cell functions correlate with a decline in somatic tissue regeneration capacity during aging. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we obtained quisecent MuSCs from young, old, geriatric mice for high resolution mass spectrometry Bruker timsTOF Pro. By comparison of young proteome to old MuSCs proteome or geriatric MuSC proteome, we identified the pathways that are differentially during aging.

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Project description:During aging, the regenerative capacity of skeletal muscle decreases due to intrinsic changes in muscle stem cells (MuSCs) and alterations in their niche. Here, we used quantitative mass spectrometry to characterize intrinsic changes in the MuSC proteome and remodeling of the MuSC niche during aging. We generated a network connecting age-affected ligands located in the niche and cell surface receptors on MuSCs. Thereby, we revealed signaling via Integrins, Lrp1, Egfr and Cd44 as the major cell communication axes perturbed through aging. We investigated the effect of Smoc2, a secreted protein that accumulates with aging, originating from fibro-adipogenic progenitors. Increased levels of Smoc2 contribute to the aberrant Itgb1/MAPK signaling observed during aging, thereby causing impaired MuSC functionality and muscle regeneration. By connecting changes in the proteome of MuSCs to alterations of their niche, our work will enable a better understanding of how MuSCs are affected during aging.

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Changes of the muscle stem cell niche during aging

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Enhancer rewiring orchestrates inflammation and loss of cell identity during muscle stem cell aging [Hi-C]

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