Reduced growth rate of aged muscle stem cells is associated with impaired mechanosensitivity.

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.

---Mechanosensitivity of aged muscle stem cells.

During aging, skeletal muscle tissue progressively declines in mass, strength, and regenerative capacity. Decreased muscle stem cell (MuSC) number and impaired function might underlie the aging-related muscle wasting and impaired regenerative capacity. As yet, the search for factors that regulate MuSC fate and function has revealed several biochemical factors within the MuSC niche that may be responsible for the decline in MuSC regenerative capacity. This decline cannot be explained by environmental factors solely, as the MuSC potential to regenerate muscle tissue is not reversed by changing the biochemical MuSC niche composition. Here we discuss the likeliness that during physical exercise, MuSCs within their niche are subjected to mechanical loads, in particular pressure and shear stress, as well as associated deformations. We postulate that these physical cues are involved in the activation and differentiation of MuSCs as these cells contain several transmembrane sensor proteins that have been shown to be mechanosensitive in other cell types, that is, endothelial cells and osteoprogenitors. We will specifically address age-related changes in mechanosensing in MuSCs and their niche. Insight in the physical cues applied to the MuSCs in vivo, and how these cues affect MuSC fate and function, helps to develop new therapeutic interventions to counterbalance age-related muscle loss. This requires an approach combining two- and three-dimensional live cell imaging of MuSCs within contracting muscle tissue, mathematical finite element modeling, and cell biology. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:632-641, 2018.