Pathogenic role of anti –signal recognition protein and anti–3‐Hydroxy‐3‐methylglutaryl‐CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies

ObjectiveImmune‐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. MethodsMuscle 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. ResultsIn 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 tota...
Source: Annals of Neurology - Category: Neurology Authors: Tags: Research Article Source Type: research