Highlights d Development of a mouse model of pancreatic adenocarcinoma (PDA)-induced cachexia d Model develops progressive wasting associated with advancing pancreas pathology d Induction of cachexia in adult KPP mice models tissue loss in PDA cancer patients d Gene ontology of cachectic muscles from KPP mice resembles that of PDA patients

Plasma membrane repair is a conserved cellular response mediating active resealing of membrane disruptions to maintain homeostasis and prevent cell death and progression of multiple diseases. Cell membrane repair repurposes mechanisms from various cellular functions, including vesicle trafficking, exocytosis, and endocytosis, to mend the broken membrane. Recent studies increased our understanding of membrane repair by establishing the molecular machinery contributing to membrane resealing. Here, we review some of the key proteins linked to cell membrane repair.

Various injuries to the neural tissues can cause irreversible damage to multiple functions of the nervous system ranging from motor control to cognitive function. The limited treatment options available for patients have led to extensive interest in studying the mechanisms of neuronal regeneration and recovery from injury. Since many neurons are terminally differentiated, by increasing cell survival following injury it may be possible to minimize the impact of these injuries and provide translational potential for treatment of neuronal diseases. While several cell types are known to survive injury through plasma membrane repair mechanisms, there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair as a therapy in neurons. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in skeletal muscle. Interestingly, recombinant human MG53 (rhMG53) can be applied exogenously to increase membrane repair capacity both in vitro and in vivo. Increasing the membrane repair capacity of neurons could potentially minimize the death of these cells and affect the progression of various neuronal diseases. In this study we assess the therapeutic potential of rhMG53 to increase membrane repair in cultured neurons and in an in vivo mouse model of neurotrauma. We found that a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair both in vitro and in vivo. These findings provide direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for neuronal injury.

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Idiopathic immune myopathies (IIM) represent a group of disorders causing chronic inflammation and significant damage to skeletal muscle due to an unchecked autoimmune response. The main challenge slowing study of IIM is an understanding of the pathogenic mechanism responsible for initiation and progression of skeletal muscle inflammation. Two mouse models of IIM have recently provided new insights into the pathogenesis of the disease. The synaptotagmin VII null (Syt VII−/−) mouse is characterized by defects in membrane resealing and presents with a mild form myositis at 2 months of age. A more robust model of IIM combines knock‐out of Syt VII with a FoxP3 mutation resulting in a mouse with impaired membrane resealing and regulatory T‐cell deficiency. Adoptive transfer of lymphocyte preparations isolated from this double mutant mouse model to recombination‐activating gene 1 (RAG‐1) null mice results in severe skeletal muscle inflammation. Plasma membrane resealing is a highly conserved mechanism allowing an injured cell to survive following a disruption to the lipid bilayer that compromises barrier function. Given the importance of plasma membrane barrier function in preventing exposure of intracellular antigens to the immune system, specifically in an immune‐compromised environment, it is possible that compromised sarcolemma resealing could drive pathogenesis of IIM. We show, for the first time, that a deficiency in T‐regulatory cells is not sufficient to induce sarcolemma fragility, however, purified antibodies against critical proteins facilitating the sarcolemma repair process are sufficient to reduce membrane integrity. We also demonstrate that sarcolemma integrity is reduced in distal skeletal muscle in the absence of inflammation in our novel murine model of IIM. We have established by direct ELISA that auto‐antibodies against multiple proteins involved in sarcolemma repair are elevated in IIM patient sera and find that exogenous delivery of IIM positive patient serum can compromise sarcolemma resealing in healthy skeletal muscle. These findings represent a novel mechanism that drives the progression of IIM when decreased sarcolemma integrity induces a vicious cycle of antigen presentation that directly contributes to the pathophysiology of idiopathic immune myopathies.Support or Funding InformationNIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases Award Number F31AR071745This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.