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Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.

Original publication

DOI

10.1007/s00401-017-1731-9

Type

Journal article

Journal

Acta Neuropathol

Publication Date

10/2017

Volume

134

Pages

655 - 666

Keywords

Acetylcysteine, Adult, Aged, Animals, Cell Line, Cytokines, Dermatomyositis, Female, Free Radical Scavengers, Freund's Adjuvant, Humans, Inflammation, Interferon-beta, Male, Mice, Inbred BALB C, Middle Aged, Mitochondria, Muscle Weakness, Muscle, Skeletal, Nervous System Autoimmune Disease, Experimental, Reactive Oxygen Species, Transcriptome