Skeletal muscle injury-repair and regeneration is a multi-cellular process that involves repair of acute injury to the sarcolemma, mobilization of satellite cells to replace the lost-muscle fibers, and control of fibrotic remodeling for maintenance of muscle integrity. In muscular dystrophy, compromised sarcolemma integrity or membrane repair triggers the cascade of muscle degeneration that incurs progressive, severe morbidity and ultimately mortality. Developing therapeutic approaches to improve sarcolemma integrity while facilitating regeneration of injured muscle fibers remain a major challenge in muscle physiology research. This project builds on the discovery of MG53, a member of the TRIM-family protein, as an essential component of the cell membrane repair machinery. MG53 functions in vesicle trafficking and facilitates the nucleation of intracellular vesicles to sites of membrane disruption for repair patch formation. Native MG53 is present in blood circulation, at levels directly correlating with injury or secretory activity of the muscle. Administration of recombinant human MG53 (rhMG53) protein protects muscle fibers and stem cells from injury, and reduces muscle fibrosis in the mdx mouse model. Our research with MG53 over the past few years has established a potential tri-functional role for MG53 in muscle injury-regeneration, as a facilitator to repair acute sarcolemma injury, a contributor to activate satellite cells during the early phase of muscle injury, and a modulator of fibrosis by controlling fibroblast differentiation associated with chronic muscle injury. We envision that targeting the tri-functional role of MG53 will have advantage over the current paradigms for treating muscular dystrophy.
In Aim 1, we will determine the pathways that transduce the newly identified myokine function of MG53 into activation of satellite cells in response to acute muscle injury; define the mechanisms that underlie MG53?s function in regulating fibrosis during chronic muscle injury; and test if non-invasive interventions can modulate circulating MG53 levels toward muscle injury-regeneration. If circulating MG53 plays a role in satellite cell activation, we predict that ischemia-preconditioning that releases MG53 without muscle injury, or inducible secretion of MG53 from a transgenic mouse model, will effectively activate satellite cells and muscle regeneration following injury.
In Aim 2, we will evaluate the safety and efficacy for sustained elevation of MG53 in circulation to preserve muscle integrity/satellite cell activation/fibrosis control in animal models of muscular dystrophy. Fulfillment of the studies in this project will advance the biology of MG53 in muscle injury-repair and regeneration, and lay the foundation for our translational approach for targeting MG53 function for treatment of muscular dystrophy.

Public Health Relevance

Development of a therapeutic approach to facilitate muscle injury-repair and regeneration represents an important area of biomedical and clinical research. Studies outlined in this proposal aim to define the function of a novel cell membrane repair gene in muscle physiology and disease, with the goal to translate the basic biology findings into potential treatment of muscular dystrophy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-C (02)M)
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Boyce, Amanda T
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Ohio State University
Schools of Medicine
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