The dysferlinopathies result from mutations in the dysferlin gene the produce a variety of clinical presentations. While understanding the disease mechanisms involved in dysferlinopathies has been a subject of extensive study, there are many aspects of the pathophysiology and the molecular mechanisms that lead to muscle dysfunction that are not clearly resolved. One of these proposed pathogenic mechanisms is the loss of the muscle cell membrane repair response in the absence of dysferlin. This project has focused on resolving fundamental mechanisms of muscle cell membrane repair, how dysferlin could contribute to repair and if these mechanisms can be targeted for treatment of dysferlinopathy. The studies from the previous project year increased our understanding of dysferlin’s function in membrane repair and also conducted proof-of-concept experiments to test potential therapeutic approaches that may increase membrane repair in dysferlin-deficient muscle. We examined if activating survival kinase signaling can increase membrane repair in dysferlinopathy patient myoblasts cells and found that activing the pathway could compensate for the absence of dysferlin in this cell model. We used these cells to resolve appropriate dosing levels to treat a mouse model of dysferlinopathy so that we can establish if this approach could be a good potential therapeutic for dysferlinopathy.
Another series of experiments tested the impact of autoantibodies targeting membrane repair proteins on dysferlinopathy pathology. Our results from our previous studies showed that antibodies against TRIM72/MG53 (a dysferlin binding protein that contributes to membrane repair) appear in the serum of human dysferlinopathy patients, much as they do in idiopathic inflammatory myopathy (IIM) patients. In this project year, we found that these TRIM72/MG53 antibodies could compromise membrane repair in dysferlinopathy patient myoblast cells, which could provide a potential mechanism to accelerate the progression of dysferlinopathy. Moreover, we also found that there are antibodies against other membrane repair proteins in serum samples from dysferlinopathy patients and that these antibodies can also compromise membrane repair in skeletal muscle. These findings suggest that this could be a general mechanism contributing to the progression of the disease, which would make it an excellent target for therapeutic intervention.