Engineered pediatric human muscle models the interferon-driven transcriptome of juvenile dermatomyositis

Abstract Juvenile dermatomyositis (JDM) is a rare pediatric autoimmune disease characterized by a strong type I interferon (IFN) signature in muscle. Mechanistic and therapeutic discovery has been limited by the lack of a clinically relevant disease model. To address this, we tested whether IFN treatment of a human muscle-derived microphysiological system (myobundles) recapitulates the transcriptional profile of JDM muscle. Principal component analysis of RNA sequencing from healthy and JDM muscle along with IFN-treated and untreated myobundles revealed separation of healthy and untreated samples from JDM and IFN-treated samples. JDM muscle exhibited 4,121 differentially expressed genes (DEGs, p adj <0.05) compared to healthy muscle, of which 56.2% showed concordant differential expression in IFNβ-treated and 30.0% in IFNα-treated myobundles. Hallmark pathway analysis demonstrated concordant directional changes between JDM muscle and IFN-treated myobundles. IFN and inflammatory pathways were most upregulated; oxidative phosphorylation, fatty acid metabolism, and adipogenesis were downregulated, though not reproducible across sites. Normalized enrichment score correlations between JDM muscle and IFN-treated myobundles were strongly positive ( r = 0.63, p =1 × 10 − 6 for IFNα; r = 0.67, p = 1.3 × 10 − 7 for IFNβ). These findings indicate that IFN-treated myobundles, particularly with IFNβ, mirror key transcriptional features of JDM muscle and provide a needed muscle-centric platform to study IFN-driven mechanisms and therapeutic targets.