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Acta Neuropathol. 2017 Oct;134(4):655-666. doi: 10.1007/s00401-017-1731-9. Epub 2017 Jun 16.

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

Author information

1
Institut de Physiologie EA 3072, Service de Physiologie et d'Explorations Fonctionnelles, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. alain.meyer7@gmail.com.
2
Centre de Référence des Maladies Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. alain.meyer7@gmail.com.
3
Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France. alain.meyer7@gmail.com.
4
Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.
5
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Illkirch, France.
6
Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Neuro-Musculaires Paris Est, Assistance Public - Hôpitaux de Paris (AP-HP)DHU I2B, Sorbonne Universités UPMC Univ Paris 06, Inserm, UMR 974, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
7
Service de Neurologie, Centre de Référence des Maladies Neuro-musculaires, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
8
Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
9
Institut de Physiologie EA 3072, Service de Physiologie et d'Explorations Fonctionnelles, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
10
Service de Médecine Interne, Centre de Compétences de Maladies Systémiques Rares, Hôpitaux Privés de Metz, Metz, France.
11
Institut National de la Santé et de la Recherche Médical, U905 Université de Normandie, Rouen, France.
12
Centre de Référence des Maladies Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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.

PMID:
28623559
DOI:
10.1007/s00401-017-1731-9
[Indexed for MEDLINE]

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