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

Area of Science:

• Immunology and Muscle Biology
• Molecular Mechanisms of Inflammatory Myopathies

Background:

• Idiopathic immune myopathies (IIM) involve immune-driven muscle damage, characterized by myofibre necrosis and aberrant MHC expression.
• Upregulation of IFNγ and senescence pathways is observed in anti-synthetase syndrome (ASS) and inclusion body myositis (IBM).

Purpose of the Study:

• To investigate the link between IFNγ, Major Histocompatibility Complex (MHC) expression, and muscle atrophy in IIM.
• To elucidate the mechanism of IFNγ-induced muscle stem cell (MuSC) dysfunction and explore therapeutic interventions.

Main Methods:

• Transcriptomic analysis of muscle biopsies from IIM patients (ASS and IBM).
• In vivo mouse models with chronic IFNγ release and acute muscle injury.
• In vitro studies using cultured human MuSCs and treatment with JAK1/2 inhibitors.

Main Results:

• IFNγ expression correlated with myofibre atrophy in ASS and IBM; overexpression in MuSCs suggests their response to IFNγ.
• IFNγ exposure in mice impaired muscle repair, reduced muscle weight and myofibre diameter, and promoted fibrosis.
• In vitro, IFNγ impaired human MuSC proliferation and fusion, induced senescence, and inhibited MyoD expression and cell cycling.
• Ruxolitinib (JAK1/2 antagonist) blocked IFNγ-induced MHC-II expression, restored MuSC proliferation, reduced senescence, and improved muscle parameters in vivo.

Conclusions:

• IFNγ mediates muscle atrophy in inclusion body myositis (IBM) through JAK1/2 pathways, impairing MuSC function and promoting senescence.
• JAK1/2 inhibition represents a potential therapeutic strategy for IBM, offering an alternative to conventional immunosuppressants.