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

Mohammad Haroon,René J.P Musters,Astrid D Bakker,Richard T Jaspers,Fabien Le Grand,Jenneke Klein-Nulend,Heleen E Boers,Niek G.C Bloks,Willem M.H Hoogaars,Lorenzo Giordani,Louise Deldicque,Katrien Koppo

doi:10.18632/aging.203830

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.

Highlights

Aging-associated reduction in muscle regeneration after injury and loss of muscle mass is referred to as sarcopenia [1, 2]
Exponential growth rates of muscle stem cell (MuSC) isolated from young mice and aged MuSCs were determined to assess whether aged MuSCs were intrinsically impaired in their ability to proliferate
We showed that aged MuSCs exhibited lower gene expression of Pax7, cyclin D1 (Ccnd1), cyclin-dependent kinase 4 (Cdk4), and higher Myog expression, whereas cyclin-dependent kinase inhibitor 2A (Cdkn2a) expression was slightly but not significantly higher in aged MuSCs compared to young MuSCs

Summary

Introduction

Aging-associated reduction in muscle regeneration after injury and loss of muscle mass is referred to as sarcopenia [1, 2]. Prime mechanistic factors underlying the loss of muscle mass are myofiber atrophy and loss of myofibers [2]. This myofiber loss is attributed to an impaired regenerative capacity of aged muscle and associated muscle stem cells (MuSCs) [3]. Muscle regeneration relies on the proper functioning of myofibers and their associated MuSCs, which are selfrenewing skeletal muscle precursor cells involved in www.aging-us.com muscle growth, repair, and regeneration [4, 5]. MuSCs lose their potential to regenerate the damaged myofiber [7], resulting in an imbalance between muscle degeneration and regeneration leading to a loss of muscle mass [8]. The mechanism of reduced MuSC function with ageing is still not fully understood

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