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Objective  Muscle inflammation is a feature in myositis and Duchenne muscular dystrophy ( DMD ). Autoimmune mechanisms are thought to contribute to muscle weakness in patients with myositis. However, a lack of correlation between the extent of inflammatory cell infiltration and muscle weakness indicates that nonimmune pathologic mechanisms may play a role. The present study focused on 2 micro RNA  (mi RNA ) sets previously identified as being elevated in the muscle of patients with  DMD —an “inflammatory” mi RNA  set that is dampened with glucocorticoids, and a “dystrophin‐targeting” mi RNA  set that inhibits dystrophin translation—to test the hypothesis that these mi RNA s are similarly dysregulated in the muscle of patients with myositis, and could contribute to muscle weakness and disease severity.    Methods  A major histocompatibility complex class I–transgenic mouse model of myositis was utilized to study gene and mi RNA  expression and histologic features in the muscle tissue, with the findings validated in human muscle biopsy tissue from 6 patients with myositis. Mice were classified as having mild or severe myositis based on transgene expression, body weight, histologic disease severity, and muscle strength/weakness.    Results  In mice with severe myositis, muscle tissue showed mononuclear cell infiltration along with elevated expression of type I interferon and  NF ‐κB–regulated genes, including  Tlr7  (3.8‐fold increase,  P  < 0.05). Furthermore, mice with severe myositis showed elevated expression of inflammatory mi RNA s (miR‐146a, miR‐142‐3p, miR‐142‐5p, miR‐455‐3p, and miR‐455‐5p; ~3–40‐fold increase,  P  < 0.05) and dystrophin‐targeting mi RNA s (miR‐146a, miR‐146b, miR‐31, and miR‐223; ~3–38‐fold increase,  P  < 0.05). Bioinformatics analyses of chromatin immunoprecipitation sequencing (ChIP‐seq) data identified at least one  NF ‐κB consensus element within the promoter/enhancer regions of these mi RNA s. Western blotting and immunofluorescence analyses of the muscle tissue from mice with severe myositis demonstrated reduced levels of dystrophin. In addition, elevated levels of  NF ‐κB–regulated genes,   TLR 7 , and mi RNA s along with reduced dystrophin levels were observed in muscle biopsy tissue from patients with histologically severe myositis.    Conclusion  These data demonstrate that an acquired dystrophin deficiency may occur through  NF ‐κB–regulated mi RNA s in myositis, thereby suggesting a unifying theme in which muscle injury, inflammation, and weakness are perpetuated both in myositis and in  DMD .

Muscle Weakness in Myositis: MicroRNA‐Mediated Dystrophin Reduction in a Myositis Mouse Model and Human Muscle Biopsies