Regulation of skeletal muscle apoptotic signaling and programmed cell death

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Apoptosis is a form of cell death that plays an important role in controlling tissue development and homeostasis; however, dysfunction occurs in numerous diseases. Mitochondria are important mediators of cell survival and death given their role in producing energy, altering the levels of damaging reactive oxygen species (ROS), and releasing factors that directly promote apoptosis. Recent evidence suggests that increased apoptosis in skeletal muscle contributes to the muscle atrophy and possibly the functional deficiencies associated with neuromuscular disorders, cardiovascular disease, and aging. Skeletal muscle has the remarkable ability to undergo various cellular adaptations including alterations in mitochondrial biogenesis/content in response to physiological and pathophysiological stimuli. Independent studies have shown that reduced mitochondrial content along will increased oxidative stress and apoptosis occurs in several skeletal muscle disorders and aging. In contrast, physical activity can increase mitochondrial biogenesis, improve ROS removal, and decrease apoptosis in skeletal muscle. Collectively, these studies suggest that mitochondrial content may be an important factor dictating cell function and survival. However, the direct effect of altered mitochondrial content on oxidative stress and apoptosis has not been studied in any cell type including skeletal muscle. The proposed research will alter mitochondrial content in vitro (in muscle and non-muscle cells) and in vivo (skeletal muscle) using several different approaches. Using state-of-the-art methods, we will comprehensively examine how apoptosis and oxidative stress (at a basal state and in response to cellular stress) are altered in conditions of low or high mitochondrial content. Further, the efficacy of regular physical activity (which induces mitochondrial biogenesis in muscle) will be evaluated as a strategy to inhibit skeletal muscle oxidative stress, apoptosis, and atrophy in response to chemical stress and a pathophysiological condition of muscle atrophy. Ultimately, the findings of this research could have important implications for understanding the molecular mechanisms that regulate skeletal muscle apoptosis and physiological adaptations that occur with exercise.