Cell Death Mechanisms in Skeletal Muscle

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Apoptosis and autophagy are two biological mechanisms that participate in cell death. Although these pathways have commonly been studied independently, recent evidence suggests that they are highly integrated. Autophagy and apoptosis occur in skeletal muscle during a variety of conditions. Interestingly, apoptotic and autophagic signaling are essential for proper muscle formation and function, but also have a role in skeletal muscle degradation and dysfunction. There is also evidence that autophagy influences apoptosis, which may affect muscle recovery and remodeling after stress. Currently, the roles of these two death-associated pathways on skeletal muscle are not well known. Autophagy and apoptosis also appear to be altered by exercise; however, this phenomenon is not well understood. The proposed work will use cell culture and animal models to investigate the direct influence of autophagic mechanisms on skeletal muscle cell differentiation, adaptation, recovery, and susceptibility to apoptotic stress. In vitro experiments using cells with altered autophagy signaling will examine the role of autophagy on muscle cell differentiation, as well as the interplay between autophagy and apoptosis during skeletal muscle formation and cell death. Furthermore, a specific transgenic animal model with reduced skeletal muscle autophagy will be utilized. These in vivo experiments will determine the role of autophagy and apoptosis on skeletal muscle recovery to acute strenuous exercise. In addition, these experiments will specifically investigate the role of autophagy on exercise training-associated changes in skeletal muscle adaptation and apoptotic susceptibility. The proposed work will significantly improve our comprehension of cell death processes in skeletal muscle, as well as provide fundamental knowledge and understanding of skeletal muscle differentiation, development, adaptation, and function.