Louiza Arouche-Delaperche1, Yves Allenbach1,2, Damien Amelin1, Corinna Preusse3, Vincent Mouly1, Wladimir Mauhin1, Gaelle Dzangue Tchoupou1, Laurent Drouot4, Olivier Boyer4, Werner Stenzel3, Gillian Butler-Browne1, Olivier Benveniste1,2. 1. 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. 2. 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. 3. Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany. 4. Department of Immunology, University of Normandy UNIROUEN, National Institute of Health and Medical Research U1234, Rouen University Hospital, Rouen, France.
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. INTERPRETATION: 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.
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: tumornecrosis 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. INTERPRETATION: 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: Iago Pinal-Fernandez; David R Amici; Cassie A Parks; Assia Derfoul; Maria Casal-Dominguez; Katherine Pak; Richard Yeker; Paul Plotz; Jose C Milisenda; Josep M Grau-Junyent; Albert Selva-O'Callaghan; Julie J Paik; Jemima Albayda; Andrea M Corse; Thomas E Lloyd; Lisa Christopher-Stine; Andrew L Mammen Journal: Arthritis Rheumatol Date: 2019-06-18 Impact factor: 10.995
Authors: Ingrid E Lundberg; Manabu Fujimoto; Jiri Vencovsky; Rohit Aggarwal; Marie Holmqvist; Lisa Christopher-Stine; Andrew L Mammen; Frederick W Miller Journal: Nat Rev Dis Primers Date: 2021-12-02 Impact factor: 52.329