{"title":"The Effect of Anti-3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) Human Autoantibodies on Muscle Regeneration in Mice.","authors":"Sarah Julien, Honorine Tomasevic, Thara Jaworski, Rachid Zoubairi, Jeremie Martinet, Laurent Drouot, Olivier Boyer","doi":"10.1002/mus.70016","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction/aims: </strong>Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies (aAbs) are pathogenic in immune-mediated necrotizing myopathy (IMNM), partly through complement activation. C5 inhibition did not restore muscle strength in mice or patients with overt IMNM, suggesting additional pathogenic mechanisms. In vitro studies have suggested that anti-HMGCR aAbs might impair myoblast fusion and myotube differentiation, but this has not been investigated in vivo. This study aimed at assessing the impact of anti-HMGCR aAbs on muscle regeneration in a mouse model of muscle necrosis.</p><p><strong>Methods: </strong>Muscle necrosis was induced by cardiotoxin (CTX) injection into the gastrocnemius of C57BL/6 or C5-deficient C57BL/10 mice. Mice received intraperitoneal injections of IgG purified from an anti-HMGCR<sup>+</sup> IMNM patient every other day. At Days 3 and 6, muscle strength was assessed, blood collected, and muscles frozen for histological analyses.</p><p><strong>Results: </strong>In C5-deficient mice, anti-HMGCR<sup>+</sup> IgG did not impair muscle regeneration after CTX-induced muscle damage. In contrast, in complement-competent mice, aAbs reduced muscle strength (p = 0.0047), prolonged the presence of myofiber necrosis at Days 3 and 6 (p = 0.0415 and p = 0.0103), and decreased the number of Pax7<sup>+</sup> (p = 0.0317) and MyoG<sup>+</sup> (p = 0.0079) regenerating fibers by more than 50% at Day 6.</p><p><strong>Conclusion: </strong>These findings establish the cytotoxicity of anti-HMGCR aAbs on regenerating muscle cells through a primarily complement-mediated mechanism, without directly impairing cellular regeneration per se. Given the still unmet medical needs of IMNM, C5 or upstream complement-targeted therapies early in the disease course, as well as aAb reduction, B/plasma cell depletion via CAR-T cells or bispecific antibodies deserves further clinical investigation.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Muscle & Nerve","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/mus.70016","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction/aims: Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies (aAbs) are pathogenic in immune-mediated necrotizing myopathy (IMNM), partly through complement activation. C5 inhibition did not restore muscle strength in mice or patients with overt IMNM, suggesting additional pathogenic mechanisms. In vitro studies have suggested that anti-HMGCR aAbs might impair myoblast fusion and myotube differentiation, but this has not been investigated in vivo. This study aimed at assessing the impact of anti-HMGCR aAbs on muscle regeneration in a mouse model of muscle necrosis.
Methods: Muscle necrosis was induced by cardiotoxin (CTX) injection into the gastrocnemius of C57BL/6 or C5-deficient C57BL/10 mice. Mice received intraperitoneal injections of IgG purified from an anti-HMGCR+ IMNM patient every other day. At Days 3 and 6, muscle strength was assessed, blood collected, and muscles frozen for histological analyses.
Results: In C5-deficient mice, anti-HMGCR+ IgG did not impair muscle regeneration after CTX-induced muscle damage. In contrast, in complement-competent mice, aAbs reduced muscle strength (p = 0.0047), prolonged the presence of myofiber necrosis at Days 3 and 6 (p = 0.0415 and p = 0.0103), and decreased the number of Pax7+ (p = 0.0317) and MyoG+ (p = 0.0079) regenerating fibers by more than 50% at Day 6.
Conclusion: These findings establish the cytotoxicity of anti-HMGCR aAbs on regenerating muscle cells through a primarily complement-mediated mechanism, without directly impairing cellular regeneration per se. Given the still unmet medical needs of IMNM, C5 or upstream complement-targeted therapies early in the disease course, as well as aAb reduction, B/plasma cell depletion via CAR-T cells or bispecific antibodies deserves further clinical investigation.
期刊介绍:
Muscle & Nerve is an international and interdisciplinary publication of original contributions, in both health and disease, concerning studies of the muscle, the neuromuscular junction, the peripheral motor, sensory and autonomic neurons, and the central nervous system where the behavior of the peripheral nervous system is clarified. Appearing monthly, Muscle & Nerve publishes clinical studies and clinically relevant research reports in the fields of anatomy, biochemistry, cell biology, electrophysiology and electrodiagnosis, epidemiology, genetics, immunology, pathology, pharmacology, physiology, toxicology, and virology. The Journal welcomes articles and reports on basic clinical electrophysiology and electrodiagnosis. We expedite some papers dealing with timely topics to keep up with the fast-moving pace of science, based on the referees'' recommendation.