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16.06.2017 | Original Paper | Ausgabe 4/2017

Acta Neuropathologica 4/2017

IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis

Zeitschrift:
Acta Neuropathologica > Ausgabe 4/2017
Autoren:
Alain Meyer, Gilles Laverny, Yves Allenbach, Elise Grelet, Vanessa Ueberschlag, Andoni Echaniz-Laguna, Béatrice Lannes, Ghada Alsaleh, Anne Laure Charles, François Singh, Joffrey Zoll, Evelyne Lonsdorfer, François Maurier, Olivier Boyer, Jacques-Eric Gottenberg, Anne Sophie Nicot, Jocelyn Laporte, Olivier Benveniste, Daniel Metzger, Jean Sibilia, Bernard Geny

Abstract

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.

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Zusatzmaterial
Supplementary material 1 (EPS 4871 kb) Supplementary figure 1. Transcriptomic analysis of deltoid muscle biopsy from DM patients and controls. Heat map representation of the cluster of genes, the expressions of which are down-regulated and up-regulated in DM deltoid muscles compared to controls. Black squares indicate the clusters represented in figure 1.
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Supplementary material 2 (EPS 1700 kb) Supplementary figure 2. Characterisation of cellular inflammation, fibre necrosis, and atrophy in DM, non-DM IM, and control patients.Cellular inflammation score (a), number of necrotic fibres (per 1000 fibres) (b), and mean cross-sectional surface of myofibres (c) determined in deltoid biopsies of DM (n=16, black bars), non-DM IM (n=14, grey bars), and control (n=16, white bars) patients. (d) Transcript levels of genes encoding proteins involved in muscle atrophy (FOXO1, FOXO3, REDD1, MURF, and ATROGIN) in deltoid biopsies of DM (n=9, black bars), non-DM IM (n=9, grey bars), and control (n=9, white bars) patients. Correlation between aerobic capacities determined on a cycloergometer and inflammation score (e), number of necrotic fibre (f), and cross-sectional area (g) in muscle of DM patients. * p <0.05 vs. controls by one-way ANOVA and post hoc Newman–Keuls range test.
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Supplementary material 3 (EPS 1491 kb) Supplementary figure 3. Mitochondrial respiration of human myotubes treated with TNF-α or IL-6 with and without the ROS scavenger N-acetyl cysteine.Maximal mitochondrial respiration (Vmax) and mitochondrial respiration with TMPD and ascorbate (VTMPD) in LHCN-M2 human myotubes exposed 3 days to TNF-α (10 ng/ml) (a) or IL-6 (100 ng/ml) (b) in the presence (black bars) or absence (grey bars) of the ROS scavenger N-acetyl cysteine (NAC 1 mM). Untreated LHCN-M2 human myotubes (white bars) (n=6). * p <0.05 vs. controls by one-way ANOVA and post hoc Newman–Keuls test for pro-inflammatory cytokines stimulated cells.
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Supplementary material 4 (XLSX 131 kb)
401_2017_1731_MOESM4_ESM.xlsx
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