Clues to Drivers of Juvenile Dermatomyositis: Genetic Alterations after Type I Interferon and JAK Inhibitor Treatment in Pediatric Bioengineered Skeletal Muscle

To better understand the pathogenesis of juvenile dermatomyositis (JDM) we examined the genetic alterations that result from exogenous IFN I exposure in pediatric skeletal muscle. We compared untreated healthy pediatric donor-derived myobundles with those treated with IFN I as well as with JAKi baricitinib and tofacitinib. We used bulk mRNA sequencing to evaluate how IFN I and treatment with JAKi influence healthy and JDM skeletal muscle gene expression and show IFNβ leads to a greater pro-inflammatory gene response than IFNα in pediatric skeletal muscle. As a type I interferon gene signature is established in JDM, downregulated oxidative phosphorylation, myogenesis, and contractile protein gene expression is implicated in JDM pathology. These genetic changes are partially reversed by JAK inhibitors, baricitinib and tofacitinib, with baricitinib leading to greater genetic alteration than tofacitinib. Our findings show that analysis of differential gene expression in bioengineered pediatric skeletal muscle can inform our knowledge of JDM pathogenesis and therapeutic effects. We compared untreated healthy pediatric donor-derived myobundles with those treated with IFN I as well as with JAKi baricitinib and tofacitinib. Bulk mRNA sequencing to evaluate how IFN I and treatment with JAKi influence healthy and JDM skeletal muscle gene expression.