Muscle weakness in myositis: microRNAs mediate dystrophin reduction in MHC class I transgenic mouse model and human muscle biopsies

Muscle inflammation is a feature in myositis and Duchenne Muscular Dystrophy (DMD). Autoimmune mechanisms are thought to contribute to myositis muscle weakness. However, the lack of correlation between inflammatory infiltrates and muscle weakness indicates a role for non-immune pathological mechanisms. We previously identified two microRNA sets elevated in DMD muscle. One is an "inflammatory" set that is dampened with glucocorticoids; the other is a "dystrophin-targeting" set that inhibits dystrophin translation. Here we test the hypothesis that these miRNAs are similarly dysregulated in myositis muscle and contribute to muscle weakness and disease severity. We utilized the MHC class I transgenic myositis mouse model and validated findings in 6 myositis patient muscle biopsies. Mice were classified as mild or severe based on transgene expression, weight, histological severity, and muscle strength/weakness. Severe myositis mice show mononuclear cell infiltration along with elevated expression of Type 1 IFN and NF-B-regulated genes including Tlr7 (3.8-fold, p