Examining the Role of Autophagy in Skeletal Muscle Cell Death and Differentiation
McMillan, Michael Elliott
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Autophagy is catabolic process which sequesters large portions of cytoplasm as well as selected organelles and proteins for degradation. Recently, autophagy has been a topic of much debate owing to conflicting evidence regarding its role in cell death signaling. Interestingly, both apoptotic signaling and altered autophagy have been observed in states associated with muscular atrophy and dysfunction. However, the cross-talk between these two cell death-related processes is not well understood in skeletal muscle. Interestingly, myogenesis and the ability of muscle to regenerate, requires myoblast differentiation, a process which requires highly regulated cell death signaling. The interplay between autophagy and apoptosis and the integrated role between these two supposed cell death systems during myoblast differentiation is unknown. The purpose of this thesis was to examine the relationship between autophagy and apoptotic signaling during myoblast differentiation as well as during myotube apoptotic stress and recovery. Chapter II reveals that autophagy is induced during myoblast differentiation, but more importantly, is required for muscle cell differentiation and protection against cell death. Chapter III determined that the induction of autophagy is required for the regulation of apoptosis during muscle cell differentiation through the prevention of mitochondrial-mediated apoptotic signaling. Chapter IV established that autophagy is required for the protection and recovery of muscle cell viability and mitochondrial function during moderate levels of apoptotic stress. Together this thesis supports autophagy as a regulator of apoptotic processes in skeletal muscle. Furthermore, this thesis highlights a role for autophagy in skeletal muscle differentiation and recovery from apoptotic stress.