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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 microRNA<\/jats:styled-content> (miRNA<\/jats:styled-content>) sets previously identified as being elevated in the muscle of patients with DMD<\/jats:styled-content>\u2014an \u201cinflammatory\u201d miRNA<\/jats:styled-content> set that is dampened with glucocorticoids, and a \u201cdystrophin\u2010targeting\u201d miRNA<\/jats:styled-content> set that inhibits dystrophin translation\u2014to test the hypothesis that these miRNA<\/jats:styled-content>s are similarly dysregulated in the muscle of patients with myositis, and could contribute to muscle weakness and disease severity.<\/jats:p><\/jats:sec>Methods<\/jats:title>A major histocompatibility complex class I\u2013transgenic mouse model of myositis was utilized to study gene and miRNA<\/jats:styled-content> 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.<\/jats:p><\/jats:sec>Results<\/jats:title>In mice with severe myositis, muscle tissue showed mononuclear cell infiltration along with elevated expression of type I interferon and NF<\/jats:styled-content>\u2010\u03baB\u2013regulated genes, including Tlr7<\/jats:italic> (3.8\u2010fold increase, P<\/jats:italic> < 0.05). Furthermore, mice with severe myositis showed elevated expression of inflammatory miRNA<\/jats:styled-content>s (miR\u2010146a, miR\u2010142\u20103p, miR\u2010142\u20105p, miR\u2010455\u20103p, and miR\u2010455\u20105p; ~3\u201340\u2010fold increase, P<\/jats:italic> < 0.05) and dystrophin\u2010targeting miRNA<\/jats:styled-content>s (miR\u2010146a, miR\u2010146b, miR\u201031, and miR\u2010223; ~3\u201338\u2010fold increase, P<\/jats:italic> < 0.05). Bioinformatics analyses of chromatin immunoprecipitation sequencing (ChIP\u2010seq) data identified at least one NF<\/jats:styled-content>\u2010\u03baB consensus element within the promoter\/enhancer regions of these miRNA<\/jats:styled-content>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<\/jats:styled-content>\u2010\u03baB\u2013regulated genes, TLR<\/jats:styled-content>7<\/jats:italic>, and miRNA<\/jats:styled-content>s along with reduced dystrophin levels were observed in muscle biopsy tissue from patients with histologically severe myositis.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>These data demonstrate that an acquired dystrophin deficiency may occur through NF<\/jats:styled-content>\u2010\u03baB\u2013regulated miRNA<\/jats:styled-content>s in myositis, thereby suggesting a unifying theme in which muscle injury, inflammation, and weakness are perpetuated both in myositis and in DMD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41215","type":"journal-article","created":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T04:56:02Z","timestamp":1580705762000},"page":"1170-1183","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Muscle Weakness in Myositis: MicroRNA\u2010Mediated Dystrophin Reduction in a Myositis Mouse Model and Human Muscle Biopsies"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4161-8213","authenticated-orcid":false,"given":"Travis B.","family":"Kinder","sequence":"first","affiliation":[{"name":"George Washington University and Children\u2019s National Hospital Washington DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-2068","authenticated-orcid":false,"given":"Christopher R.","family":"Heier","sequence":"additional","affiliation":[{"name":"George Washington University and Children\u2019s National Hospital Washington DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7151-0102","authenticated-orcid":false,"given":"Christopher B.","family":"Tully","sequence":"additional","affiliation":[{"name":"Children\u2019s National Hospital Washington DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-806X","authenticated-orcid":false,"given":"Jack H.","family":"Van der Muelen","sequence":"additional","affiliation":[{"name":"Children\u2019s National Hospital Washington DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6470-5139","authenticated-orcid":false,"given":"Eric P.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Binghamton University, Binghampton, New York, and ReveraGen BioPharma Rockville Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1601-8489","authenticated-orcid":false,"given":"Kanneboyina","family":"Nagaraju","sequence":"additional","affiliation":[{"name":"Binghamton University, Binghampton, New York, and ReveraGen BioPharma Rockville 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