Duchenne muscular dystrophy (DMD) and other dystrophies arising from mutations in the dystrophin/dystroglycan complex produce pathology, at least in part, due to sarcolemmal membrane fragility. Several other forms of muscular dystrophy have been linked to defective membrane repair including those linked to mutations in caveolin-3 (Cav3) and dysferlin in human patients. A therapeutic approach to increase the capacity of muscle cells to reseal their membranes following physiological levels of mechanical stress could address both of these mechanisms leading to improvement of muscular dystrophy pathology. We recently discovered that mitsuguimin 53 (MG53), a muscle-specific TRIM-family protein, is an essential component of the acute membrane repair machinery. MG53 nucleates recruitment of intracellular vesicles to the injury site for membrane patch formation. We found that MG53 can interact with dysferlin to facilitate its membrane repair function, and some of the membrane repair defects in muscular dystrophy are associated with altered interaction between MG53, caveolin-3 and dysferlin. In new data presented in this application, we find that acute injury many cell types leads to exposure of a phosphatidylserine (PS) signal to the extracellular space that can be detected by purified recombinant human MG53 protein (rhMG53), allowing rhMG53 to locate to the injury sites and increase the capacity of targeted cells to repair membrane damage. These findings led us to hypothesize that: rhMG53 and native MG53 can bind to PS that flows through membrane disruptions to increase the membrane repair capacity of cell membranes. This action would allow rhMG53 to act as a therapeutic agent for the treatment of muscular dystrophy. We will test this possibility with two specific Aims.
Aim 1 will establish the mechanism(s) contribute to the extracellular action of rhMG53 in membrane resealing.
Aim 2 will test if rhMG53 can provide therapeutic benefit in a faithful mouse model of DMD. Our studies here provide important steps forward in understanding the mechanisms of extracellular MG53 action in membrane repair and can help to establish if rhMG53 could effectively treat a model of muscular dystrophy. The ability for rhMG53 to increase membrane repair in non-muscle cells suggests that rhMG53 may act as a platform technology that could target a number of different disease states where compromised membrane integrity and/or necrotic cell death contribute to the underlying pathology.
Muscular dystrophies are severe genetic disorders that are associated with defects in muscle cell membrane integrity or a reduced capacity for muscle to repair damage that occurs during normal contraction. Duchenne muscular dystrophy (DMD) is an inherited, progressive muscle wasting disorder that leads to compromised muscle structure, decreased muscle function, loss of independence and death in the second decade of life in affected patients. DMD is the most prevalent form of muscular dystrophy and is the most common lethal genetic disease as approximately 20,000 children worldwide are born with DMD annually. DMD and other muscular dystrophies represent a truly unmet medical need as there is currently no cure for any form of muscular dystrophy. Current treatment is designed to help prevent or reduce deformities in the joints and the spine and to allow people with DMD to remain mobile as long as possible. However, none of these treatments have any efficacy on the underlying pathology. Attempts to produce therapeutics targeting this unmet medical need have been complicated by the lack of knowledge of the basic biology of cell membrane repair. The discovery of MG53 as a key component of the muscle membrane repair machinery has opened a new therapeutic approach for treatment of muscular dystrophy. Our research effort proposed in this project will generate the proof-of-principle data that recombinant MG53 protein can be an effective therapeutic agent for treatment of muscular dystrophy.
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