Development of an in vitro model for skeletal muscle hypertrophy

Webster, Matthew
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The skeletal muscles are one of the most important tissues in the body. They enable us to move, perform work, and interact with other people. One of the unique features of skeletal muscles is their plasticity. They are able to adapt to an increased work load by increasing their size (hypertrophy), or to become more resistant to fatigue by increasing their oxidative capacity. The processes that facilitate muscle hypertrophy are quite diverse, and are not yet fully understood. There is currently a need to examine these processes further so that we can develop effective measures both to promote increased hypertrophy, as well as prevent muscle atrophy. The focus of this research project was to develop an in vitro system for muscle hypertrophy that accurately models the physiologic processes that are observe in vivo. Cells were cyclically stretched, and stretch is a key modulator of the hypertrophy response in vivo. I performed a series of experiments to examine two events during the hypertrophy process. First, I examined the effect of cyclic stretch on p21[Superscript WAF1] promoter activity in C2C12 myotubes. Previous research has indicated that p21 [Superscript WAF1] expression is up-regulated during work-overload in vivo, and thus a candidate for a stretch responsive promoter. The second research aim was to examine the process of myogenesis within the in vitro model of skeletal muscle hypertrophy. Particular focus was paid to the expression of the myogenic regulatory factors (MRFs) and other cell regulatory proteins. The results of these experiments indicate that the model system that was used accurately models the in vivo process of skeletal muscle hypertrophy. The ultimate goal of my research into the molecular mechanisms controlling hypertrophy was to construct the intracellular signaling cascades that transmit physical stimuli from the extracellular matrix into increased expression of stretch responsive genes.