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

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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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Acknowledgements

We thank Doulaye Dembele for his assistance in analysing microarray data and Nadia Messaddeq for electron microscopy analyses. Transcriptomic analyses were performed by the IGBMC Microarray and Sequencing platform, which is supported by the “France Génomique” National Infrastructure, funded as part of the “Investissements d’Avenir” program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-0009). This work was supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Collège de France, the ADIRAL, and by French state funds through the Agence Nationale de la Recherche ANR-10-LABX-0030-INRT under the frame program Investissements d’Avenir labelled ANR-10-IDEX-0002-02. G.L. was supported by the Agence Nationale de la Recherche (2010BLAN1108-01).

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401_2017_1731_MOESM1_ESM.eps

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.

401_2017_1731_MOESM2_ESM.eps

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.

401_2017_1731_MOESM3_ESM.eps

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.

Supplementary material 4 (XLSX 131 kb)

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Meyer, A., Laverny, G., Allenbach, Y. et al. IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis. Acta Neuropathol 134, 655–666 (2017). https://doi.org/10.1007/s00401-017-1731-9

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