Identifying new targets to sustain skeletal muscle function

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PROJECT SUMMARY Skeletal muscle atrophy is a loss of muscle mass and corresponding loss of function that occurs in response to diverse stimuli including disuse/immobility, glucocorticoid treatment, cancer, aging, and denervation. Denervation is a significant contributor to muscle atrophy in trauma, neuromuscular diseases, and age- associated sarcopenia in humans. Muscle satellite cells possess the unique capacity to proliferate and regenerate in settings of muscle injury, and recent studies indicate some degree of constitutive incorporation even into healthy, uninjured myofibers, suggesting a role in muscle maintenance as well. This study aims to (a) identify additional mechanisms causing muscle atrophy during acute and chronic denervation, (b) identify functional and genomic changes that occur in muscle satellite cells during atrophy, and (c) assign functional roles for novel satellite cell-enriched genes, with the expectation of identifying novel targets for minimizing atrophic changes and/or sustaining or enhancing muscle satellite cell proliferative and regenerative capacity. To achieve these goals, we will conduct a longitudinal analysis of transcriptional changes occurring in skeletal muscle and in skeletal muscle satellite cells during denervation atrophy. This work aligns closely with the mission of the NIH and several of its agencies, specifically to understand the causes of neurologic and musculoskeletal disease, and to reduce the burden of these conditions through the identification and development of new therapies. The applicant’s own long-term professional goal is to establish a career conducting research related to human disease with an emphasis on identifying translational opportunities to improve diagnosis and treatment, while providing dedicated and compassionate clinical care for those affected. Pursuing the work proposed in this application will allow him to learn more about skeletal muscle and satellite cell biology, and to develop facility using contemporary sequencing and informatics tools to identify pathways involved in atrophy and regeneration. These methods can be applied in numerous contexts in future work, as research and clinical medicine become increasingly influenced by genomics and reliance on synthesis of complex data. The day-to- day data analysis requirements of this project will be complemented by longitudinal coursework in statistical analysis and design of clinical experiments, practical experience with sequencing platforms, opportunities to work and train with others in the fields of both informatics and myogenesis, and opportunities to share findings at conferences and meetings. These skills will significantly broaden the scope of questions the applicant will be able to address now and in the future, and will strengthen his ability to use large, unbiased data sets to identify novel changes during disease pathogenesis with an eye toward new clinical interventions.