TRIM72/MG53 autoantibodies represent a novel disease mechanism compromising sarcolemmal membrane repair in Limb Girdle Muscular Dystrophy


Translational Research

Poster Number: 167


Noah Weisleder, PhD, Ohio State Universtiy, Hannah Bulgart, BS, Ohio State University, Kassidy Banford, BS, Ohio State University, Kevin McElhanon, PhD, Ohio State University, ,

Background: Limb Girdle Muscular Dystrophy Autosomal Recessive 2 (LGMDR2, previously LGMD2B) results from mutations in the dysferlin gene that can display a variety of clinical presentations. The extent of symptoms and age of onset can vary and there have been a variety of designations for dysferlinopathies, including Miyoshi Myopathy, Distal Myopathy with Anterior Tibial Onset, Proximodistal weakness, Pseudometabolic myopathy, and HyperCKemia. Dysferlin acts in the sarcolemmal membrane repair response and loss of dysferlin leads to compromised sarcolemma integrity, myocyte death and muscular dystrophy. While understanding the disease mechanisms involved in dysferlinopathies has been a subject of intense study, there are many aspects of the pathophysiology that lead to muscle dysfunction that are not clearly resolved. Understanding these mechanisms is essential for effective management of LGMDR2 and development of new therapeutic approaches. We recently published that autoantibodies against TRIM72/MG53, a dysferlin binding partner protein that contributes to membrane repair, can compromise membrane repair and that they appear in the serum of human immune-mediated myopathy (IMM) patients (McElhanon, et al., JCI, 2020). Objectives: Given the similarities in pathological presentation of IMM and LGMDR2 we tested if autoantibodies against TRIM72/MG53 appear in the LGMDR2 patient serum and if these antibodies could compromised membrane repair in skeletal muscle. Results: ELISA testing of 106 LGMDR2 patient serum samples revealed 17.9% had highly elevated MG53/TRIM72 autoantibodies. Similar results were seen in mouse models of LGMDR2. Serum from LGMDR2 patients or mouse models, as well as exogenous anti-dysferlin antibodies, compromise sarcolemmal membrane repair in laser wounding repair assays. Compromised repair is dependent on TRIM72/MG53 antibodies as depletion of these antibodies from serum samples removes these effects on membrane repair. This antibody mediated compromised membrane repair could represent a therapeutic target for LGMDR2 as we find poloxamer compounds known to increase sarcolemma integrity can reduce these impact of TRIM72/MG53 antibodies in a LGMD2R mouse model. Conclusions: Our results reveal the autoantibodies against TRIM72/MG53 that compromised sarcolemma repair could represent a novel disease mechanism in LGMDR2. We find targeting membrane integrity minimizes these effects, indicating a new potential therapeutic intervention.