Aging-associated impairment of muscle mechanosensitivity: Implications for muscle protein synthesis and regeneration
Authors:   , Haroon Mohammad 
Published: March 2023

A well-functioning skeletal muscle is vital for independent and healthy living. However, aging is associated with a decline in muscle mass and regenerative capacity, known as sarcopenia. Sarcopenia is characterized by reduced force-generating capacity leading to lower mobility. Skeletal muscle has the ability to regenerate after injury, as well as to adapt its size to physical loads. This process of regeneration and adaptation declines with aging as a result of reduced muscle plasticity, leading to skeletal muscle loss and function. The etiology of sarcopenia is multifactorial, but decreased muscle stem cell (MuSC) function is thought to play a role in the development of sarcopenia. Little is known about the alterations leading to declined MuSC function with age.
The aims of this thesis were: 1) To review the role of biophysical cues in determining MuSC function, and how aging affects the mechanosensitivity of MuSCs. 2) To investigate whether MuSCs are subjected to mechanical cues within their niche during muscle stretch-shortening, and whether mechanical cues produce a physiological response in MuSCs. 3) To explore the role of the glycocalyx in the MuSC mechanoresponse. 4) To assess the role of mechanical cues in MuSC function, and determine age-related alterations within MuSC that are involved in their declined regenerative function. 5) To determine the effects of tensile strain and shear stress on nitric oxide (NO) production and gene expression by myotubes, and the role of Ca2+ and ROCK signaling herein.
The MuSC in the MuSC niche in connection to extra‐muscular connective tissue are likely be subjected to mechanical loads during physical exercise. The presence of several mechanosensory complexes within the MuSC membrane combined with evidence of mechanoresponsiveness of MuSCs indicates that mechanical loads and subsequent cellular deformations are important co‐determinants of MuSC function. We postulated that mechanosensing of the aging MuSC may become dysfunctional due to intrinsic changes of the MuSC by alterations in expression levels of transmembrane and/or cytoskeletal proteins (chapter 2). Our results showed that upon myofiber stretch, MuSCs within their native niche, attached to the basal lamina and sarcolemma of the host myofiber, are subjected to compression as well as tensile and shear deformations (chapter 3). Moreover, mechanical loading by pulsating fluid shear stress (PFSS) induces NO production, gene expression (i.e., c-Fos, Cdk4, and IL-6), and ERK 1/2 and p38 MAPK signaling. We also showed that the glycocalyx is likely involved in fluid shear stress-induced myoblast deformation and modulation of gene expression (chapter 4). The results of this thesis showed that aged MuSCs exhibited a reduced growth rate and integrin-α7 expression, as well as a lower number of phospho-paxillin clusters than young MuSCs. Furthermore, aged MuSCs exhibited reduced adhesion strength. Moreover, YAP signaling and mechanoresponsiveness were altered in aged MuSCs (chapter 5). We also showed that mechanical loading by cyclic strain (CS) and PFSS induced a differential mechanoresponse and production of factors involved in MuSC recruitment in primary myotubes (chapter 6). Moreover, calcium signaling was involved in PFSS-induced NO production and IL-6 expression, and ROCK activation in PFSS-induced COX2 and IL-6 expression.
This thesis shows that besides biochemical cues, mechanical cues, which are inherent to skeletal muscles, are transduced to MuSCs and elicit a mechanoresponse in these cells. The process of mechanosensing is altered with aging in MuSCs. Our results highlight the importance of mechanical cues in regulating MuSC function and age-related cell-intrinsic alterations in MuSC function leading to declined muscle regeneration and muscle wasting. Taken together, we identified an impairment in mechanosensitivity of aged MuSCs as a previously unknown mechanism in the declined MuSC function and muscle regeneration, that most likely contributes to sarcopenia.