Dysfunctional mechanisms of the mitochondrial redox-sensitive signaling response to exercise in aged skeletal muscle

Abstract: Dysfunctional mechanisms of the mitochondrial redox-sensitive signaling response to exercise in aged skeletal muscle. Individual: This career development award application details training and scientific research for Matthew D. Campbell, Ph.D. a skeletal muscle and mitochondrial biologist in the Radiology department at the University of Washington, Seattle. His short-term goals are to take his background in mitochondria, redox biology, and contraction dynamics in aged muscle and expand them with tools evaluating tissue metabolism and mitochondrial protein interactions using novel 3D engineered tissue and in vivo mouse models. His long-term goals are to form an independent research laboratory focused on the mechanisms of muscle contraction/relaxation dynamics that interact with metabolic function in muscle. Research: Aging in skeletal muscle is a complex pathology involving redox signaling, metabolic deficits, oxidative damage, neuromuscular junction defects, and protein expression and interaction changes. Previous work by Dr. Campbell has shown that restoring basal redox state improves mitochondrial and skeletal muscle function. This proposal builds on his previous work to establish that dysfunctional redox-sensitive signaling alters substrate utilization following exercise (Aim 1), impacts beta oxidation and TCA cycle flux (Aim 2), and mitochondrial protein interactions (Aim 3). Career Development Plan: The proposed work in this application would support Dr. Campbell’s short-term and long-term goals by enhancing his current expertise in muscle and mitochondrial function with work focused on developing novel human induced pluripotent stem cell lines, assays of in vivo whole tissue metabolism, dissecting mechanisms of redox signaling, and generating/analyzing large datasets of metabolomics and peptide/protein interactions. His professional development activities will include technical training, formal coursework, guest lecturing on mitochondrial metabolism, presentation of his research at local and national conferences, grant writing and review, routinely scheduled lab meetings and individual meetings with his mentors. Research Environment: The University of Washington offers an outstanding environment for the training in muscle research and aging and includes the Northwest Metabolomics Research Center, Center for Translational Muscle Research, and a Nathan Shock Centers of Excellence in the Basic Biology of Aging. Dr. Campbell’s mentorship team includes senior faculty members that are well-known and respected for their work in 3D engineered tissue, metabolism, and mitochondrial protein interactions.