The dysferlinopathies are a class of muscular dystrophies that result from mutations in the dysferlin gene that display 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. The studies from this 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 survival kinase signaling can increase membrane repair in dysferlinopathy. Recent studies in our laboratory examined the effects of modulating specific on the membrane repair response in skeletal and cardiac muscle. We found that initiation of membrane repair requires the activation of intracellular signaling response and that increasing the activation of can increase membrane repair and compensate for the compromised membrane integrity associated with the absence of dystrophin in vitro.
Additional experiments tested the impact of autoantibodies targeting membrane repair proteins on dysferlinopathy. Our previous results show that antibodies against TRIM72/MG53 (a dysferlin binding protein that contributes to membrane repair) can compromise membrane repair and that they appear in the serum of human immune-mediated myopathy (IMM) patients. Serum from these IMM patients can also compromise skeletal muscle membrane repair. Dysferlinopathies show similar pathological hallmarks as seen in IMM. This lead to the hypothesis that generation of antibodies against membrane repair proteins can compromise the repair response and exacerbate the pathology associated with dysferlinopathy. We found that autoantibodies against TRIM72/MG53 appear in dysferlin-deficient mouse models and in dysferlinopathy patient serum samples.
These studies increased our understanding of the function of dysferlin protein in the regulation of various cellular functions that are essential for the normal function of skeletal muscle. These findings all made initial steps forward in testing potential therapeutic approaches can increase membrane repair capacity in the skeletal muscle of dysferlin-deficient muscle cells. Establishing additional mechanisms of dysferlin function and activity in restoring membrane repair capacity could have direct translational value as an indicator that such approaches could be adapted for future therapy approaches.