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.