Pathogenic role of anti–signal recognition protein and anti–3‐Hydroxy‐3‐methylglutaryl‐<scp>C</scp>o<scp>A</scp> reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies

TLDR

Immune‑mediated necrotizing myopathies are linked to anti‑SRP or anti‑HMGCR antibodies, whose titers correlate with disease activity. The study aimed to determine whether these antibodies contribute to muscle damage and to elucidate their pathogenic role through coculture experiments. Researchers examined patient muscle biopsies for atrophy and regeneration using fiber‑size measurements and neonatal myosin staining, and performed in‑vitro cocultures of muscle cells with the antibodies, assessing myotube surface area, gene expression, and cytokine profiles. Antibody‑positive biopsies showed numerous small fibers, and in vitro the antibodies induced atrophy, upregulated MAFbx and TRIM63, elevated TNF, IL‑6, and ROS, and impaired myoblast fusion by reducing IL‑4/IL‑13, a defect that was fully rescued by adding these cytokines, highlighting mechanisms that drive muscle dysfunction and suggesting targeted therapeutic avenues. Published in Ann Neurol 2017;81:538‑548.

Abstract

Immune-mediated necrotizing myopathies (IMNM) may be associated with either anti-signal recognition protein (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies (Abs), and the titer of these Abs is correlated with disease activity. We investigated whether anti-SRP and anti-HMGCR Abs could be involved in muscle damage.Muscle biopsies of patients were analyzed for atrophy and regeneration by measuring fiber size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell coculture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles.In muscle biopsies of patients with anti-SRP+ and anti-HMGCR+ Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed. In vitro, anti-SRP and anti-HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and TRIM63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: tumor necrosis factor, interleukin (IL)-6, and reactive oxygen species. In the presence of anti-SRP or anti-HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL-4 and IL-13. The addition of IL-4 and/or IL-13 totally rescued fusion capacity.These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. Ann Neurol 2017;81:538-548.