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Session: Session 2

IFNgamma causes mitochondrial dysfunction and oxidative stress in myositis

Catalina ABAD2, Sophie BENARD5, Rachid ZOUBAIRI2, Bernard GENY4, Christian BOITARD6, Andrew MAMMEN3, Alain MEYER4, Olivier BOYER1, Iago PINAL-FERNANDEZ3, Clément GUILLOU1, Gwladys BOURDENET2, Laurent DROUOT2, Pascal COSETTE1, Margherita GIANNINI4, Lea DEBRUT4, Laeticia JEAN2

1Univ Rouen Normandy, INSERM US51, CNRS UAR 2026, HeRacLeS PISSARO, Rouen, France
2Univ Rouen Normandy, INserm UMR1234, FOCIS Center of Excellence, PAn'THER, Rouen, France
3Muscel Diseases Unit, National Institute of Arthritis and Musculoskeletal and Skin Disaeses, National Institutes of Health, Bethesda, United States
4Translational Medicine Federation of Strasbourg, Team 3072, Faculty of Medicine, Strasbourg, France
5Univ Rouen Normandy, Inserm, CNRS, HeRacLes PRIMACEN US 51 UAR 2026, Rouen, France
6Cochin Institute, Paris Descartes University, Sorbonne Paris Cité, Inserm U1016, Paris, France

Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Quantitative proteomic analysis between Icos-/- NOD and Icos+/+ NOD mice muscle at different time point (8, 25 and 35 weeks) brought to light a profound metabolic dysregulation in myofibers, especially in mitochondrial functions. Levels of multiple proteins belonging to the respiratory chain complex (I, II, III, IV and V) were significantly reduced in the muscle of Icos-/- NOD mice compared to Icos+/+ NOD mice. To validate mass spectrometry results and understand the severe mitochondrial dysfunction, different approaches have been designed. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS). Blocking IFNg in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Together, our results suggest that ROS and mitochondrial dysfunction are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.