Spatial transcriptomic analysis of muscle biopsy from treatment-naive juvenile dermatomyositis patients reveals mitochondrial abnormalities despite disease-related interferon driven signature

Abstract

ObjectivesThis study aimed to investigate the spatial transcriptomic landscape of muscle tissue from treatment-naive juvenile dermatomyositis (JDM) patients in comparison to healthy paediatric muscle tissue. MethodsMuscle biopsies from three JDM patients and three age-matched controls were analysed using the Nanostring GeoMx(R) Digital Spatial Profiler. Regions of interest were selected based on muscle fibres without immune cells, immune cell infiltration and CD68+ macrophage enrichment. Differential gene expression, pathway analysis and pathways clustering analysis were conducted. Key findings were validated in 19 cases of JDM using immunohistochemistry and chemical stains, and a bulk RNAseq dataset of four cases of JDM. ResultsJDM muscle tissues exhibited significant interferon pathway activation and mitochondrial dysfunction compared to controls. A 15-gene interferon signature was significantly elevated in JDM muscle and macrophage-enriched regions, correlating with clinical weakness. In contrast, mitochondrial dysregulation, characterized by downregulated respiratory chain pathways, was present regardless of interferon activity or muscle strength. The interferon-driven and mitochondrial signatures were replicated in an independent RNAseq dataset from JDM muscle; lack of association between interferon signature and mitochondrial dysregulation was validated in 19 cases by conventional staining methods. Clustering analysis revealed distinct transcriptomic profiles between JDM and control tissues, as well as between JDM patients with varying clinical phenotypes. ConclusionsThis study highlights mitochondrial dysfunction as a consistent pathological feature in JDM muscle, which may be independent of interferon-driven inflammation. These findings highlight the potential for mitochondrial-targeted therapies in JDM management and emphasise the need for further studies to explore their therapeutic value. KEY MESSAGESWhat is already known on this topic O_LIJuvenile dermatomyositis (JDM) involves interferon-driven inflammation and immune-mediated muscle damage. C_LIO_LIMitochondrial abnormalities in blood immune cells persist despite treatment and contribute to disease pathology. C_LI What this study adds O_LIMitochondrial dysfunction is present in both muscle fibres and tissue-infiltrating immune cells within JDM muscle. C_LIO_LIThese abnormalities are detectable even in clinically less severe muscle weakness. C_LIO_LIDegree of mitochondrial abnormality at transcript and protein level may be independent of strength of IFN-driven signal. C_LIO_LIMitochondrial dysregulation detected at transcriptional level correlates with abnormal transcription of muscle (sarcomere) and the subcellular peroxisome organelle. C_LI How this study might affect research, practice, or policy O_LITargeting mitochondrial dysfunction could enhance treatment outcomes for JDM, especially in patients whose disease is refractory to current therapies. C_LIO_LIInsights from this study support the development of stratification tools to detect aspects of pathology which are not tightly correlated with IFN-driven pathology. C_LI