THE ROLE OF CELLULAR SENESCENCE IN AGING MUSCLE CELLS

Abstract

Skeletal muscle is a highly plastic tissue that relies on its resident muscle stem cell population, known as satellite cells (SC), for its timely repair and regeneration. During aging, there is a decline in muscle regenerative capacity that is largely attributed to the loss of SC content and function. These aberrations are thought to contribute to the aging-related decline in skeletal muscle mass and strength. Cellular senescence, which is characterized by a state of irreversible cell cycle arrest and the presence of a senescence-associated secretory phenotype (SASP), has emerged as a potential factor in the dysfunction of SCs with aging. The purpose of this thesis was to explore the mechanisms and consequences of cellular senescence in SCs by examining the cellular, metabolic, and genetic activity of skeletal muscle myoblasts. Through a model of DNA damage-based senescence, we demonstrated that senescent myoblasts experience significant impairments in proliferation and differentiation that were maintained for extended periods of time in culture. Furthermore, we found alternative senescence signalling pathways that highlighted the importance of a multi-marker approach when classifying cellular senescence. Building on these findings, we then investigated the intracellular and extracellular metabolic profile of senescent myoblasts. These cells displayed a significantly altered exometabolome that included the elevated release of several aging-associated metabolites. Notably, one of these extracellular senescence-associated metabolites, oleic acid, was capable of upregulating multiple SASP genes that are implicated in muscle regeneration. The results of this work showed that senescent myoblasts release SASP factors that are capable of intercellular communication, which provided the foundation for our next study. Here, we evaluated the potential for extracellular vesicles secreted by senescent myoblasts (SEVs) to act as mediators of the SASP. SEVs were packaged with miRNAs implicated in senescence signalling that upregulated anti-apoptotic gene expression in recipient cells, revealing a potential mechanism for EV-mediated intercellular communication from senescent myoblasts. Collectively, these findings demonstrate the multifaceted role of cellular senescence in skeletal muscle cells and underscore its implications for the aging-related dysfunction of satellite cells.