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bioRxiv · 10.1101/2021.12.16.472927

Interferon-gamma mediates skeletal muscle lesions through JAK/STAT pathway activation in inclusion body myositis

Hou, C.·Periou, B.·Gervais, M.·Berthier, J.·Baba-Amer, Y.·Souvannanorath, S.·Malfatti, E.·Relaix, F.·bencze, M.·Authier, F. J.
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Abstract

Dysimmune and Inflammatory Myopathies (DIMs) are acquired idiopathic myopathy associated with immune response dysregulation. Inclusion Body Myositis (IBM), the most common DIMs, is characterized by endomysial infiltrates of cytotoxic T lymphocytes CD8, muscle type II-interferon (IFN{gamma}) signature, and by the lack of response to immunomodulatory therapies. We showed that IBM was pathologically characterized by the presence of chronic degenerative myopathic features including myofiber atrophy, fibrosis, adipose involution, and the altered functions of skeletal muscle stem cells. Here, we demonstrated that protracted systemic exposure to IFN{gamma} delayed muscle regeneration and led to IBM-like muscular degenerative changes in mice. In vitro, IFN{gamma} treatment inhibited the activation, proliferation, migration, differentiation, and fusion of myogenic progenitor cells and promoted their senescence through JAK-STAT-dependent activation. Finally, JAK-STAT inhibitor, ruxolitinib abrogated the deleterious effects of IFN{gamma} on muscle regeneration, suggesting that the JAK-STAT pathway could represent a new therapeutic target for IBM.

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Hou, C., Periou, B., Gervais, M., Berthier, J., Baba-Amer, Y., Souvannanorath, S., Malfatti, E., Relaix, F., bencze, M., Authier, F. J.. 2021-12-16. Interferon-gamma mediates skeletal muscle lesions through JAK/STAT pathway activation in inclusion body myositis. https://doi.org/10.1101/2021.12.16.472927

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