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.