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

    loading  Checking for direct PDF access through Ovid


Immune‐mediated necrotizing myopathies (IMNM) are a subgroup of idiopathic inflammatory myopathies. Typically, IMNM patients suffer from an acute and severe muscle weakness with high creatine kinase levels, without extramuscular manifestations.1 By definition, they harbor characteristic pathological skeletal muscle features on muscle biopsy: dominant necrosis, myophagocytosis, and regeneration, with no or sparse lymphocytic infiltrates.4 Anti–signal recognition protein (SRP) and anti–3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) antibodies (Abs) have been specifically associated with IMNM.2 The titers of anti‐SRP and anti‐HMGCR Abs are correlated with both clinical and biological markers of disease activity.1 These observations suggest a pathogenic role for these Abs.
Treatments associating corticosteroid and immunosuppressants and/or intravenous immunoglobulin are efficient, but patients experience frequent relapses and a long disease duration, leading to a risk of muscle damage and handicap.1 A major feature in IMNM is muscle atrophy,1 which is considered to be irreversible.11
Morphological studies of muscle biopsies have shown that IMNM with either anti‐SRP+ or anti‐HMGCR+ Abs showed a large heterogeneity in fiber size,7 suggesting the presence of atrophic and/or regenerating muscle fibers.
Atrophic and regenerating fibers may be similar in size; however, their etiology is completely different. Atrophy is defined as the decrease in cell size, involving loss of contractile proteins and upregulation of transcription of genes called “atrogenes,” including ATROGIN‐1/MAFbx or TRIM63/MURF1, that are considered to be markers of atrophy.13 This phenomenon can occur in several conditions, including inflammatory states involving proinflammatory cytokines.15 In contrast, muscle regeneration occurs after an injury, and involves activation, differentiation, and fusion of satellite cells.16 The regeneration process is tightly controlled by multiple different factors, including anti‐inflammatory cytokines such interleukin (IL)‐4 and IL‐13.17
Atrophy and regeneration have never been characterized in IMNM patients with anti‐SRP and anti‐HMGCR Abs. It is crucial to investigate these mechanisms with respect to prognosis of the disease and putative therapeutic strategies.
We hypothesized that anti‐SRP and anti‐HMGCR Abs could be directly implicated in pathogenicity, and we investigated their effect on muscle regeneration and atrophy on myoblasts and differentiated myotubes in vitro.
    loading  Loading Related Articles