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Stearns-Reider_Aging Cell March 2017_ECM and aging.pdf (1.49 MB)

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

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posted on 2017-04-07, 15:21 authored by Kristen M. Stearns-Reider, Antonio D'Amore, Kevin Beezhold, Benjamin Rothrauff, Loredana Cavalli, William R. Wagner, David A. Vorp, Alkiviadis Tsamis, Sunita Shinde, Changqing Zhang, Aaron Barchowsky, Thomas A. Rando, Rocky S. Tuan, Fabrisia Ambrosio
Age-related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age-related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age-related increase in muscle stiffness drives YAP/TAZ-mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.


This work was supported by the NIH NIA Grant K01AG039477 (FA), NIEHS Grant F32ES022134 (KB), NIEHS Grant R01ES023696 (FA and AB), NIEHS Grant R01ES025529 (FA and AB), and the University of Pittsburgh Medical Center Rehabilitation Institute.



Aging Cell, 2017

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/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Engineering


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Aging Cell


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Additional Supporting Information may be found online in the supporting information tab for this article. Fig. S1 The histomorphometric analysis of collagen type III and elastin in young and old skeletal muscle. Fig. S2 DAPI and Tcf4 staining of fibroblasts isolated from the skeletal muscle of young and old mice. Fig. S3 The microarray gene expression profiling in young and old fibroblasts. Fig. S4 The expression of Pax7 & MyoD in the human muscle stem cells utilized in cell seeding experiments. Fig. S5 The resulting expression of desmin (A) and Tcf4 (B) from MuSCs seeded onto young and old decellularized and solubilized matrices. Fig. S6 The analysis of collagen composition between ECM deposited by young and old fibroblasts. Fig. S7 The dose response of latrunculin A (A) and leptomycin B (B).



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