Priority Research Paper Volume 14, Issue 1 pp 28—53
Reduced growth rate of aged muscle stem cells is associated with impaired mechanosensitivity
- 1 Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam 1081 HZ, The Netherlands
- 2 Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam 1081 LA, The Netherlands
- 3 Sorbonne Université, INSERM UMRS974, Center for Research in Myology, Paris 75013, France
- 4 Department of Physiology, Amsterdam University Medical Center VUmc, Amsterdam Cardiovascular Sciences, Amsterdam 1081 HZ, The Netherlands
- 5 Institute of Neuroscience, Université Catholique de Louvain, Louvain-la-Neuve 1348, Belgium
- 6 Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven 3001, Belgium
- 7 Faculty of Medicine and Pharmacy, NeuroMyoGène UCBL-CNRS UMR 5310, INSERM U1217, Lyon 69008, France
Received: February 24, 2021 Accepted: January 3, 2022 Published: January 13, 2022
https://doi.org/10.18632/aging.203830How to Cite
Copyright: © 2022 Haroon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Aging-associated muscle wasting and impaired regeneration are caused by deficiencies in muscle stem cell (MuSC) number and function. We postulated that aged MuSCs are intrinsically impaired in their responsiveness to omnipresent mechanical cues through alterations in MuSC morphology, mechanical properties, and number of integrins, culminating in impaired proliferative capacity. Here we show that aged MuSCs exhibited significantly lower growth rate and reduced integrin-α7 expression as well as lower number of phospho-paxillin clusters than young MuSCs. Moreover, aged MuSCs were less firmly attached to matrigel-coated glass substrates compared to young MuSCs, as 43% of the cells detached in response to pulsating fluid shear stress (1 Pa). YAP nuclear localization was 59% higher than in young MuSCs, yet YAP target genes Cyr61 and Ctgf were substantially downregulated. When subjected to pulsating fluid shear stress, aged MuSCs exhibited reduced upregulation of proliferation-related genes. Together these results indicate that aged MuSCs exhibit impaired mechanosensitivity and growth potential, accompanied by altered morphology and mechanical properties as well as reduced integrin-α7 expression. Aging-associated impaired muscle regenerative capacity and muscle wasting is likely due to aging-induced intrinsic MuSC alterations and dysfunctional mechanosensitivity.
Abbreviations
Ccnd1: cyclin D1; Cdk4: cyclin-dependent kinase 4; Cdkn2a: cyclin-dependent kinase inhibitor 2A; CFSS: constant fluid shear stress; COX2: cyclooxygenase-2; ECM: extracellular matrix; FACS: fluorescence-activated cell sorting; FAK: focal adhesion kinase; FBS: fetal bovine serum; IL-6: interleukin-6; ITGA7: integrin-α7; MuSC: muscle stem cell; MYOG: myogenin; NO: nitric oxide; pPXN: phospho-paxillin; PFSS: pulsating fluid shear stress; TAZ: transcription regulator protein 1; TEAD: TEA domain family member; Timp1: tissue inhibitor of metalloproteinase 1; YAP: Yes-associated protein.