Immune mediated necrotizing myopathies (IMNM) may be associated with either anti-SRP or anti-HMGCR antibodies (Abs) and the titre of these Abs is correlated with the disease activity. This study investigated if anti-SRP and anti-HMGCR Abs could be involved in muscle damage. Muscle biopsies of patients were analysed for atrophy and regeneration, by measuring the fibres size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, muscle cell co-culture with the Abs was performed. 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 fibres corresponding to both atrophic and regenerating fibres were observed. In vitro, anti-SRP and anti-HMGCR Abs induced muscle fibre atrophy and increased the transcription of MAFbx and Trim63. In addition, the muscle fibre atrophy was associated with high levels of inflammatory cytokines: TNF, 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.
