Aging-associated dysregulation of the hypoxia pathway limits skeletal muscle regeneration

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Project Summary/Abstract This proposal describes a five-year training program and career development plan for Dr. Indranil Sinha. Dr. Sinha is a prior trainee of a National Institute of Aging-sponsored Postdoctoral Individual National Research Service Award (F32). He is a current awardee of a Research and Education Core Grant through the Boston Pepper Center and the National Institute of Aging. He has completed clinical training in Plastic and Reconstructive Surgery and is board-certified through the American Board of Plastic Surgery. He is now embarking on a research and career development program under the mentorship of Amy Wagers, Ph.D., Professor of Medicine, Harvard Medical School. Dr. Wagers is an accomplished researcher in skeletal muscle regeneration and has a history of mentoring trainees who go on to successful, independent research careers. Additional mentoring will be provided by Dr. Shalender Bhasin, a world-renowned researcher on sarcopenia, and Dr. Laurie Goodyear, an expert on exercise physiology. Dr. Sinha's career development plan includes utilization of educational resources at Brigham and Women's Hospital, Joslin Diabetes Center, and Harvard Medical School. Career development support will also be provided by the Brigham and Women's Hospital Department of Surgery, where the principle investigator will serve as an attending physician during the period of funding. Dr. Sinha has developed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, establishment of an Aging Interest Group within Plastic Surgery, and plans for the development of independent research projects and continued research funding. Dr. Sinha is interested in developing novel treatment strategies for aging-associated loss of skeletal muscle regeneration. He is investigating mechanisms by which aging alters hypoxia pathway signaling and skeletal muscle regenerative potential in a murine model. He found that two key factors in the hypoxia pathway, aryl hydrocarbon receptor nuclear translocator (ARNT) and vascular endothelial growth factor (VEGF), are severely dysregulated in skeletal muscle in aging and may lead to a loss of skeletal muscle regenerative potential. Furthermore, using a genetically modified mouse model, he demonstrated that muscle specific loss of ARNT recapitulates diminished skeletal muscle regeneration as associated with aging. Building on these intriguing preliminary data, the central goals of this project are to (1) mechanistically define the role of hypoxia pathway signaling and its impact on muscle regeneration in aging, (2) identify interventions to restore ARNT and VEGF signaling to preserve skeletal muscle myogenic potential, and (3) determine whether muscle hypertrophy in response to exercise, which is known to require skeletal muscle regeneration and hypoxia signaling, is limited in aging secondary to loss of ARNT.