The Effect of Anti-3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) Human Autoantibodies on Muscle Regeneration in Mice.

IF 3.1 3区 医学 Q2 CLINICAL NEUROLOGY
Muscle & Nerve Pub Date : 2025-09-01 DOI:10.1002/mus.70016
Sarah Julien, Honorine Tomasevic, Thara Jaworski, Rachid Zoubairi, Jeremie Martinet, Laurent Drouot, Olivier Boyer
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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.

抗3-羟基-3-甲基戊二酰辅酶a还原酶(HMGCR)人自身抗体对小鼠肌肉再生的影响。
简介/目的:抗3-羟基-3-甲基戊二酰辅酶a还原酶(HMGCR)自身抗体(aAbs)在免疫介导的坏死性肌病(IMNM)中具有致病性,部分通过补体激活。C5抑制不能恢复明显IMNM小鼠或患者的肌肉力量,提示其他致病机制。体外研究表明,抗hmgcr单克隆抗体可能会损害成肌细胞融合和肌管分化,但尚未在体内进行研究。本研究旨在评估抗hmgcr单克隆抗体对肌肉坏死小鼠模型肌肉再生的影响。方法:将心毒素(CTX)注入C57BL/6或C57BL/10缺陷小鼠腓肠肌,诱导心肌坏死。小鼠每隔一天接受从抗hmgcr + IMNM患者纯化的IgG腹腔注射。在第3天和第6天,评估肌肉力量,采集血液,并冷冻肌肉进行组织学分析。结果:在c5缺陷小鼠中,抗hmgcr + IgG不影响ctx诱导的肌肉损伤后的肌肉再生。相比之下,在补体能力小鼠中,aAbs降低了肌力(p = 0.0047),在第3天和第6天延长了肌纤维坏死的存在(p = 0.0415和p = 0.0103),并在第6天使Pax7+ (p = 0.0317)和MyoG+ (p = 0.0079)再生纤维的数量减少了50%以上。结论:这些发现证实了抗hmgcr单克隆抗体通过补体介导的机制对再生肌肉细胞具有细胞毒性,而不直接损害细胞再生本身。鉴于IMNM、C5或上游补体靶向治疗在病程早期仍未得到满足的医疗需求,以及通过CAR-T细胞或双特异性抗体减少aAb、B/浆细胞耗竭值得进一步的临床研究。
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来源期刊
Muscle & Nerve
Muscle & Nerve 医学-临床神经学
CiteScore
6.40
自引率
5.90%
发文量
287
审稿时长
3-6 weeks
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.
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