Abstract
Mutations in the dysferlin gene are responsible for adult-onset, progressive, and recessively inherited muscular dystrophies called dysferlinopathy, which has two main phenotypes: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. The dysferlin is composed of 55 exons encoding for 2,080 amino acids. The dysferlin protein is expressed in the plasma membrane of skeletal muscles and has been reported to be involved in calcium-mediated membrane fusion and repair. We previously reported over 50 different mutations across the entire dysferlin and are focusing on these dysferlin and dysferlin-related proteins. To identify the binding partners of dysferlin, which can be working as the similar functional role, would be possible therapeutic targets to compensate the functional loss of the mutated dysferlin. Using a proteomics approach combined with a recombinant maltose-binding protein, we found a protein X that binds to a specific region of dysferlin. Next, using an ex vivo laser-injury experiment, we revealed that protein X is essential for the membrane repair of sarcolemmal damage in skeletal muscle fiber. Moreover, the injury-triggered subsarcolemmal accumulation of the protein X was regulated by dysferlin. Finally, an X-activating compound rescued the impairment of the damaged membrane repair in immortalized myoblasts established from the dysferlin-deficient patients. Collectively, the protein X is required for plasma-membrane repair and a potential therapeutic target for dysferlinopathy.
Published Version
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