title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Louiza
authors.initials: L
authors.lastname: Arouche-Delaperche
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.|Department of Internal Medicine and Clinical Immunology, University Hospital Department of Inflammation, Immunopathology, and Biotherapy, Pitié-Salpêtrière University Hospital, Public Hospital Network of Paris, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Allenbach
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Amelin
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Preusse
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Mauhin
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Gaelle Dzangue
authors.initials: GD
authors.lastname: Tchoupou
authors.affiliation: Department of Immunology, University of Normandy UNIROUEN, National Institute of Health and Medical Research U1234, Rouen University Hospital, Rouen, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Drouot
authors.affiliation: Department of Immunology, University of Normandy UNIROUEN, National Institute of Health and Medical Research U1234, Rouen University Hospital, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.affiliation: Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.|Department of Internal Medicine and Clinical Immunology, University Hospital Department of Inflammation, Immunopathology, and Biotherapy, Pitié-Salpêtrière University Hospital, Public Hospital Network of Paris, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
mesh_terms: D001284:Atrophy / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D018929:Cell Culture Techniques; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000276:immunology*; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000473:pathology / Q000502:physiology; D009135:Muscular Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis / Q000473:pathology; D012038:Regeneration / Q000502:physiology*; D018271:Signal Recognition Particle / Q000276:immunology*; D014015:Tissue Banks
chemical_list: D001323:Autoantibodies; D018271:Signal Recognition Particle; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases