Interferon-γ causes myogenic cell dysfunction and senescence in immune myopathies

Abstract

Idiopathic immune myopathies (IIM) represent a heterogeneous group of diseases, in which muscle lesions result from deregulated immune reactions. Typical histological features include myofibre necrosis, leukocyte infiltration, and aberrant myofibre Major Histocompatibility Complex (MHC) expression. To investigate the link between MHC expression, inflammation, and muscle lesions, muscle biopsies from IIM patients were analysed by transcriptomics. Both, anti-synthetase syndrome (ASS) and inclusion body myositis (IBM) displayed the upregulation of IFNγ and senescence signalling pathways. Notably, IFNγ expression significantly correlated with myofibre atrophy in ASS and IBM muscle biopsies. In addition to MHC-II expression at the myofibre sarcolemma in IBM, we observed a marked overexpression in the muscle stem cells (MuSC) population, suggesting that resident satellite cells respond to IFNγ in this condition. To examine the link between IFNγ and muscle atrophy via MuSCs, we implanted an osmotic pump chronically releasing recombinant mouse IFNγ in wild-type mice subjected to acute muscle injury. Under IFNγ exposure, post-injury muscle repair was associated with significantly reduced muscle weight and myofibre diameter, while promoting interstitial fibrosis and fat deposition. The mechanism of action of the IFNγ-induced myofibre atrophy was further investigated in vitro using cultured human MuSCs. IFNγ stimulation dramatically impaired MuSCs proliferation, fusion, and promoted cell senescence. Isolated myofibres from IFNγ-treated wild-type mice displayed a significant decrease of MyoD expression and cell cycling, suggesting that IFNγ also prevents MuSC activation. In vitro, ruxolitinib, a commercially available JAK1/2 antagonist, blocked IFNγ-induced expression of MHC-II, restored normal MuSC proliferation, and reduced β-Galactosidase activity, a marker of cell senescence. In vivo, oral delivery of ruxolitinib improved myofibre size and biomarkers of muscle atrophy. Our study provides multiple lines of evidence that IFNγ may mediate muscle atrophy in IBM patients. The identified mechanism of action involves JAK1/2 pathways, which impair MuSC function by preventing post-lesion myogenesis and promoting cell senescence. Our data suggest that repurposing JAK1/2 inhibitors may offer a new therapeutic option for treating IBM, a condition known for its resistance to classical immunosuppressant drugs, despite their effectiveness in other IIM.