PT  - JOURNAL ARTICLE
AU  - Hou, Cyrielle
AU  - Periou, Baptiste
AU  - Gervais, Marianne
AU  - Berthier, Juliette
AU  - Baba-Amer, Yasmine
AU  - Souvannanorath, Sarah
AU  - Malfatti, Edoardo
AU  - Relaix, Fréderic
AU  - Bencze, Maximilien
AU  - Authier, François Jérôme
TI  - Interferon-gamma mediates skeletal muscle lesions through JAK/STAT pathway activation in inclusion body myositis
AID  - 10.1101/2021.12.16.472927
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.16.472927
4099  - http://biorxiv.org/content/early/2021/12/16/2021.12.16.472927.short
4100  - http://biorxiv.org/content/early/2021/12/16/2021.12.16.472927.full
AB  - 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 (IFNγ) 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 IFNγ delayed muscle regeneration and led to IBM-like muscular degenerative changes in mice. In vitro, IFNγ 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 IFNγ on muscle regeneration, suggesting that the JAK-STAT pathway could represent a new therapeutic target for IBM.Competing Interest StatementThe authors have declared no competing interest.