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

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.