MG53 function in muscle aging

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PROJECT SUMMARY Elderly persons are susceptible to injury with compromised regenerative capacity of the skeletal muscle, leading to gradual muscle weakness and loss of physical activity. Impaired myogenic satellite cell function is associated with muscle aging. While it is known that exercise has many beneficial effects on aging and can improve satellite cell function, searching for the putative myogenic factors that facilitate exercise-mediated improvement of muscle function presents an attractive area for geriatric research. We know that exercise induces secretion of MG53 from skeletal muscle into circulation, which serves as a myokine to protect multiple tissues from injuries. However, exercise-induced MG53 release is severely attenuated in aging. Chronic oxidative stress associated with aging leads to MG53 aggregation that compromises MG53’s function in tissue repair and regeneration. We hypothesize rejuvenating MG53’s myokine function will have benefits to aging. We have produced a transgenic mouse model with sustained elevation of MG53 in the bloodstream, and found that these mice display remarkable muscle regeneration following injury. We have data to show that treatment with recombinant human MG53 (rhMG53) protein promotes proliferation and protects against stress-induced injury to muscle satellite cells. Therefore, we propose to test if improvement of muscle satellite cell function by MG53 can provide long-term benefits to muscle aging. Chronic oxidative stress and inflammation associated with aging may cause tissue injury and consequently the elevation of MG53 in circulation. We will use a combination of live cell imaging, proteomic, and CRISPR-gene editing tools to test if post-translational modification of MG53 in the serum can be a contributing factor for MG53’s compromised tissue repair function during aging. Outcomes of the studies in this project can lay the foundation and pave the way for our long-term goal of translating the basic findings of the benefits of MG53 into therapeutic treatments of age-related muscle dysfunctions.