IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis

Marie Maurer (1, 2, 3, 4) , Sylvain Bougoin (2, 3, 4, 1) , Tali Feferman (5) , Mélinée Frenkian (2, 3, 4, 1) , Jacky Bismuth (2, 3, 1) , Vincent Mouly (2, 3, 4, 1) , Geraldine Clairac (6) , Socrates Tzartos (7) , Elie Fadel (8, 9) , Bruno Eymard (10) , Sara Fuchs (5) , Miriam C Souroujon (11) , Sonia Berrih-Aknin (2, 3, 4, 1)

1 Institut de Myologie
2 Myology Research Center UM76
3 Thérapie des maladies du muscle strié
4 Centre de recherche en myologie
5 Department of Immunology
6 CRLCC René Huguenin - CRLCC René Huguenin
7 Institut Pasteur Hellénique
8 CCML - Centre Chirurgical Marie Lannelongue
9 HPPIT - Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique
10 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
11 Open University of Israël

Introduction: Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia. Results: A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies. Conclusions: Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

Mots clés: Anti-acetylcholine receptor antibodies; Akt; IL-6; Muscle; Myasthenia

Domaines: Génétique; Neurosciences [q-bio.NC]

Marie Maurer, Sylvain Bougoin, Tali Feferman, Mélinée Frenkian, Jacky Bismuth, et al.. IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis. Acta Neuropathologica Communications, 2015, 3 (1), pp.1. ⟨10.1186/s40478-014-0179-6⟩. ⟨hal-01116534⟩