Cell Membrane Resealing in Inflammatory Myopathy

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Project Summary Idiopathic inflammatory myopathies (IIM) are a group of inflammatory disorders characterized by muscle weakness and are associated with significant morbidity and mortality. Inflammation and muscle injury are the central features observed in histology. Both adaptive and innate immune responses are involved in the pathogenesis of IIM but the pathogenic mechanisms are not yet well defined. Current treatment options for myositis are limited and focus on the use of broad-spectrum immunosuppressive drugs that often lead to significant complications. Previous studies with synaptotagmin VII null (SytVII-/-) mice displayed impaired sarcolemmal membrane repair capacity and developed mild myositis at two months in age, suggesting that antigen presentation of internal skeletal muscle proteins may play a role in initiating or exacerbating myositis. We generated a more robust model of inflammatory myositis by combining the SytVII-/- model with scurfy mice that have a regulatory T cell deficiency (FoxP3-/Y/SytVII-/-). Adoptive transfer of lymph node cells from FoxP3- /Y/SytVII-/- mice into Rag-1-/- mice lacking both T- and B-cells results in significant muscle inflammation. This finding also links the progression of myositis with defects in sarcolemmal membrane repair. The sarcolemmal membrane repair response is a conserved response necessary to restore membrane integrity in myocytes as part of normal cellular physiology. Defects in membrane repair are linked to a variety of muscle diseases. Our previous work helped identify intracellular proteins as critical components of the membrane repair process. This application builds on our recently published work and new preliminary studies that identified novel autoantibodies in myositis patients against proteins that are essential for the membrane repair. We also established that these antibodies can alter the membrane repair capacity of skeletal muscle. We hypothesize that compromised membrane repair leads to exposure of these membrane repair proteins to the extracellular space and that the autoantibodies produced against these proteins further compromise membrane repair and exacerbate inflammation during myositis. We will test this hypothesis with three specific aims. Aim 1 will define the mechanistic role of TRIM antibodies on membrane fragility associated with myositis using various mouse models with compromised membrane repair. Aim 2 will determine if patients’ autoantibodies directed against skeletal muscle proteins linked to the membrane repair process are sufficient to compromise membrane repair. Aim 3 will test the efficacy of increasing membrane repair capacity of skeletal muscle as a novel therapeutic strategy to treat myositis. Our findings that compromised membrane repair contributes to the pathogenesis of myositis suggests a potential therapeutic strategy that could target multiple IIM.