Interferon-gamma-mediated JAK/STAT1 signalling triggers muscle damage in Inclusion Body Myositis

Dysimmune and Inflammatory Myopathies (DIMs) form a heterogeneous group of diseases with different dysregulated immune responses and interferon (IFN) signatures in skeletal muscle. Dermatomyositis (DM) is now regarded as full-blown type I interferonopathy, while inclusion body myositis (IBM) and anti-synthetase syndrome (ASS) are associated with muscle type-II IFN (IFN-II; IFNγ) signature related to the presence of IFNγ-secreting CD8 T-cells in skeletal muscles.’ Here, we showed that RNA levels of IFNg, fibrosis, and adipose involution are increased in IBM muscles. Investigating the potential role of IFNγ in the muscle defects affecting IBM patients, we investigated the potentially deleterious effects of IFNγ on myogenic progression in vitro and skeletal muscle cell repair in vivo. In vitro, IFNγ stimulation inhibited human myogenic progenitor cell activation, proliferation, migration, differentiation, and fusion. Mouse exposure to continuous systemic IFNγ administration reduced satellite cell proliferation and delayed muscle regeneration, leading to myofibre atrophy and fibrosis. Moreover, chronic IFNγ delivery promoted human myogenic cell senescence through JAK-STAT-dependent activation. Finally, the JAK-STAT inhibitor ruxolitinib abrogated both in vivo and in vitro deleterious effects of IFNγ on muscle tissue, suggesting that the JAK-STAT pathway could represent a new therapeutic target for DIMs with muscular IFN-II signature.