Cell Death Signaling in Skeletal Muscle

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Apoptosis and autophagy are two biological processes that can participate in cell death, but that also have important roles in normal tissue development, remodeling, and function. Thus, these processes must be finely controlled in order to maintain proper cell and tissue homeostasis. For example, some apoptotic signals are required for proper skeletal muscle development, but these same signals can lead to cell death if not appropriately regulated. Although autophagy can participate in cell death, in most cases autophagy is likely playing a survival role. This survival function is achieved through autophagy's ability to degrade parts of the cell and thereby reduce cellular stress. Mitophagy is a specialized form of autophagy that specifically removes/degrades mitochondria. Given that mitochondria are key regulators of apoptosis, mitophagy is able to reduce mitochondrial apoptotic signaling. Currently, the roles of autophagy and mitophagy, and interplay between autophagy/mitophagy and apoptosis, in skeletal muscle have not been fully investigated. Recently, it was found that autophagy was required for skeletal muscle stem cell maintenance and differentiation. In addition, new research has found that mitophagy is required for skeletal muscle cell differentiation. New findings from our lab show that autophagy is required for skeletal muscle differentiation by controlling apoptotic signals during the differentiation program. What is still unknown is whether mitophagy influences skeletal muscle stem cell function and differentiation through regulation of apoptotic signaling. Further, the molecular signaling mechanisms influencing these processes have not been fully defined. As such, this NSERC program will utilize cell culture and mouse models, along with advanced biochemical, cellular and molecular biology, and physiological approaches, to investigate cell death signaling in skeletal muscle formation, phenotype, adaptation, and function. More specifically, this research will investigate: 1) the function of autophagy and mitophagy on apoptotic signaling during skeletal muscle differentiation, 2) the relationship between Notch signaling, autophagy, and mitophagy in skeletal muscle differentiation, phenotype, and function, 3) the effect of autophagic and mitophagic preconditioning on skeletal muscle apoptotic susceptibility, damage, and regeneration, and 4) the influence of several key mechanisms on these responses. Moreover, this NSERC program will provide training for a number of HQP in the latest research approaches and tools. Overall, this program represents a novel research direction in the area of cell death signaling and skeletal muscle biology. Notably, this NSERC grant will continue to support the only laboratory in Canada fully devoted to studying cell death processes in skeletal muscle.