Reversing age-related dysfunction of skeletal muscle stem cells

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DESCRIPTION (provided by applicant): Sarcopenia, or age-related skeletal muscle loss, is In part due to a progressive decline in the body's ability to regenerate skeletal muscle following injury. Several lines of evidence suggest that sarcopenia may be related to chronic, muscle specific inflammation. Based on experimental models of sarcopenia, the inflammation is most likely regulated by NF-kappaB signaling mechanisms. This chronic inflammation may contribute to skeletal muscle loss over time by causing a functional impairment of skeletal muscle stem cells (SMPs) and a resultant deficit in skeletal muscle repair. The proposed study aims to further characterize temporally-regulated genes and pathways which can be manipulated in muscle to reverse the detrimental effects of age on SMPs. The first specific aim will focus on evaluating increases in NF-kappaB activity as well as inflammatory gene expression in aged SMPs. Specifically, SMPs, purified by FACS sorting, will be aged and analyzed for NF-kappaB activity, inflammatory gene expression, and correlate changes in myogenic potential in comparison to young controls. This aim will identify possible pathways by which skeletal muscle stem cell impairment occurs with aging and further characterize the role of NF-kappaB in this process. The second aim of this project is to determine if inhibition of NF-kappaB can reverse or limit age-associated impairment of SMPs. By utilizing both transgenic and pharmacologic means, this aim proposes to use a well-established mouse model of sarcopenia to evaluate if overall skeletal muscle function and SMP proliferative potential can be protected by inhibiting NF-kappaB mediated inflammation. Based on previous studies, it is hypothesized that reversing the chronic inflammation associated with muscle aging will preserve SMP proliferative potential and skeletal muscle mass and function. Relevance: Age-associated muscle loss is a major source of functional impairment in the elderly population and leads to decreased independence, ability to perform activities of daily living, and recovery following injury. By identifying methods to reverse or limit age associated muscle loss, the elderly population may keep their independence, recover quicker from injuries/hospitalizations, and overall require fewer healthcare resources.