Contribution of Membrane Repair Defects to Skeletal Muscle Inflammation

Abstract

Inflammation is a significant contributor to multiple skeletal muscle diseases, however the mechanisms that facilitate these inflammatory responses have not been fully characterized. Idiopathic immune myopathies are a group of disorders involving chronic damage to skeletal muscle due to extensive inflammation triggered by autoimmune responses and provides a model to further understand general mechanisms of inflammation. Chronic inflammation leads to degeneration of muscle structure and function resulting in severe proximal muscle weakness. T‐cell‐ and antibody‐mediated processes are involved in the progression of disease, however the mechanism leading to pathogenesis remains unknown. Two animal models have recently provided insight into the pathogenic mechanisms of myositis. Synaptotagmin VII null (SytVII−/−) mice display impaired sarcolemmal repair capacity and develop mild myositis, suggesting that antigen presentation of internal skeletal muscle proteins may play a role in initiating an autoimmune response. A more robust model of myositis combines the Syt VII−/− model with a FoxP3 mutation (FoxP3−/Y/Syt VII−/−). This mouse strain combines impaired membrane repair with regulatory T‐cell deficiency. Adoptive transfer of lymph node cells from FoxP3−/Y/Syt VII−/− mice to RAG‐1 mice lacking T‐ or B‐cells results in significant muscle inflammation. The current project examined the contribution of defective sarcolemmal repair to the pathogenesis of myositis. Sarcolemmal membrane repair is a conserved process where disruptions in the lipid bilayer are actively resealed to maintain cellular integrity. Previous studies established the cellular framework of the membrane repair process utilizes exocytotic and endocytotic vesicle trafficking to restore membrane integrity. Previous work by our lab and others identified TRIM72, a member of the Tripartite Motif family of E3 ubiquitin ligases, as a critical component of the membrane repair process. Our studies here identified novel autoantibodies against TRIM proteins in patient sera. Using an adoptive transfer model to induce myositis in mice, we show that membrane repair is compromised in skeletal muscle distal to the initial site of inflammation. We also demonstrate that exogenous delivery of antibodies against TRIM proteins can compromise membrane repair in healthy skeletal muscle. Our data indicate that defects in membrane repair associated with the progression of myositis lead to TRIM protein exposure to the extracellular space and that the autoantibodies produced against TRIM proteins further compromise membrane repair and exacerbate inflammation.Support or Funding InformationNational Institute of Arthritis and Musculoskeletal and Skin Diseases, MDA, The Ohio State University Center for Clinical and Translational Science