Determining the fiber type-specific requirements for satellite cells during skeletal muscle hypertrophy

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PROJECT SUMMARY/ABSTRACT Physical inactivity, advancing age, limb immobilization, degenerative diseases and various systemic diseases (many cancers, sepsis, HIV, COPD, kidney disease) all lead to skeletal muscle wasting. The loss of muscle mass is of major clinical importance because it leads to an increased risk for morbidity, disability, and the loss of independence; collectively contributing to a substantive increase in healthcare utilization and cost. A rapidly aging U.S population will undoubtedly lead to an increase in the prevalence of sarcopenia and the age- related systemic diseases that cause cachexia. In order to reduce concomitant increases in healthcare costs, developing interventional strategies that promote healthy aging and extend functional independence is critical. Gaining a fundamental understanding for the role of muscle stem cells (satellite cells) during muscle hypertrophy will increase the feasibility of targeting these cells and increasing their ability to promote muscle growth. Our lab previously showed that while a lack of satellite cells does not limit short-term muscle growth, satellite cells are required to support sustained growth, at least in type 2 (fast twitch) fibers. The compensatory pathways activated in the absence of satellite cell fusion to enable short-term muscle growth in type 2 fibers are of interest. In line with this, the mechanism precipitating a shift in the requirement for satellite cells during sustained muscle growth is unknown. Due to the method of overload used in previous studies, our understanding for satellite cell-mediated muscle growth is currently restricted to muscles comprised exclusively of type 2 muscle fibers. Emerging evidence suggests that these findings may not extend to type 1 (slow twitch) fibers. As type 1 fibers comprise ~50% of human skeletal muscle and are known to positively influence physical function and health, determining the role of satellite cells during type 1 fiber growth is of clinical importance. In order to address these critical gaps in our understanding of the regulation of muscle growth, the Pax7-DTA mouse strain will be used, allowing for the inducible depletion of satellite cells, and a short and long term weighted wheel running model will be used to induce hypertrophy in the plantaris (100% type 2) and the soleus (50% type 1 and 50% type 2) muscles in satellite cell deplete (SC-) and replete (SC+) mice. This design will allow me to determine (1) the fiber type-specific requirements for satellite cells during muscle growth and (2) elucidate the intracellular mechanisms regulating satellite cell independent and dependent muscle growth over a time course of muscle hypertrophy. The findings from this study will provide information necessary to evaluate the therapeutic potential of satellite cell targeted approaches, and potentially identify compensatory mechanisms enabling growth in the absence of satellite cells that may also be potential therapeutic targets. Moreover, the completion of this project will provide an outstanding training opportunity for a promising young scientist.