Investigating the Role of Type I Interferon Signaling on Muscle Disease Using Mouse Models

Dysregulated type I interferon (IFN) signaling contributes to autoimmune myositis pathogenesis. We investigated the therapeutic effects of JAK inhibitors in two mouse models. We also examined how type I IFNs affect muscle vasculature.

Myositis was induced in major histocompatibility complex class I double transgenic ([TRE-H-2K^b (H mice)/MCK-tTA (T mice)] (HT)) female mice at day 21. Mice were randomized into four groups (n = 10-11/group): baricitinib (10 mg/kg), tofacitinib (20 mg/kg), vehicle, and healthy controls. Outcomes included survival, weight, muscle strength, histopathology, and IFN-stimulated gene expression. To model IFNβ overexpression, C57BL/6 mice received AAV9-triple muscle-specific creatine kinase (tMCK)-IFNβ and were treated with vehicle or tofacitinib (40 mg/kg/day) for 10 weeks (n = 8-13/group).

Tofacitinib-but not baricitinib-significantly reduced IFN scores in mice with severe myositis (P < 0.05). Survival differed across groups (overall log-rank P < 0.01), with untreated- and baricitinib-treated HT mice showing shorter survival than BL/6 controls, whereas tofacitinib-treated mice did not differ from controls. IFNβ overexpression induced muscle inflammation (P < 0.01), reduced grip strength (P < 0.0001), and increased the IFN score (P < 0.0001) and H2Kb (P < 0.0001) expression.

Tofacitinib reduced the IFN signature, and survival in this group did not differ significantly from healthy controls, whereas untreated and baricitinib-treated HT mice showed shorter survival; functional improvement was not observed. Our results also show that type I IFN signaling contributes to muscle inflammation and weakness, making it a key driver of muscle damage and thereby reinforcing its potential as a therapeutic target.