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A major driver of DMD pathology stems from aberrant upregulation of transforming growth factor \u03b2 (TGF\u03b2) signaling. In this report, we investigated the major transducers of TGF\u03b2 signaling, i.e., receptor Smads (R-Smads), in DMD patient skeletal muscle and observed a 48-fold increase in Smad8 mRNA. Smad1, Smad2, Smad3, and Smad5 mRNA were only minimally increased. A similar pattern was observed in the muscle from the mdx5cv mouse. Western blot analysis showed upregulation of phosphorylated Smad1, Smad5, and Smad8 compared to total Smad indicating activation of this pathway. In parallel, we observed a profound diminishment of muscle-enriched microRNAs (myomiRs): miR-1, miR-133a, and miR-133b. The pattern of Smad8 induction and myomiR suppression was recapitulated in C2C12 muscle cells after stimulation with bone morphogenetic protein 4 (BMP4), a signaling factor that we found upregulated in DMD muscle. Silencing Smad8 in C2C12 myoblasts derepressed myomiRs and promoted myoblast differentiation; there was also a concomitant upregulation of myogenic regulatory factors (myogenin and myocyte enhancer factor 2D) and suppression of a pro-inflammatory cytokine (interleukin-6). Our data suggest that Smad8 is a negative regulator of miR-1, miR-133a, and miR-133b in muscle cells and that the BMP4-Smad8 axis is a driver of dystrophic pathology in DMD.<\/jats:p>","DOI":"10.3390\/ijms23147515","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:27:48Z","timestamp":1657153668000},"page":"7515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3029-0761","authenticated-orcid":false,"given":"Michael A.","family":"Lopez","sequence":"first","affiliation":[{"name":"Children\u2019s of Alabama, Birmingham, AL 35233, USA"},{"name":"Department of Pediatrics, University of Alabama at Birmingham (UAB), CHB314, 1600 7th Avenue South, Birmingham, AL 35233, USA"},{"name":"Department of Neurology, University of Alabama at Birmingham (UAB), Civitan 545C, 1530 3rd Avenue South, Birmingham, AL 35294, USA"},{"name":"UAB Center for Exercise Medicine (UCEM), University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Alabama at Birmingham (UAB), Civitan 545C, 1530 3rd Avenue South, Birmingham, AL 35294, USA"},{"name":"Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianzhen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham (UAB), CHB314, 1600 7th Avenue South, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentyna","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham (UAB), CHB314, 1600 7th Avenue South, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuad","family":"Qushair","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham (UAB), CHB314, 1600 7th Avenue South, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson","family":"Carlyle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham (UAB), CHB314, 1600 7th Avenue South, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsy","family":"Alesce","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Alabama at Birmingham (UAB), Civitan 545C, 1530 3rd Avenue South, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Conklin","sequence":"additional","affiliation":[{"name":"Children\u2019s of Alabama, Birmingham, AL 35233, USA"},{"name":"Department of Orthopedic Surgery, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Children\u2019s of Alabama, Birmingham, AL 35233, USA"},{"name":"Department of Orthopedic Surgery, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcas M.","family":"Bamman","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Alabama at Birmingham (UAB), Civitan 545C, 1530 3rd Avenue South, Birmingham, AL 35294, USA"},{"name":"UAB Center for Exercise Medicine (UCEM), University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA"},{"name":"Department of Cell, Development and Integrative Biology, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7406-5171","authenticated-orcid":false,"given":"Matthew S.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Children\u2019s of Alabama, Birmingham, AL 35233, USA"},{"name":"Department of Pediatrics, University of Alabama at Birmingham (UAB), CHB314, 1600 7th Avenue South, Birmingham, AL 35233, USA"},{"name":"UAB Center for Exercise Medicine (UCEM), University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA"},{"name":"UAB Civitan International Research Center (CIRC), Birmingham, AL 35233, USA"},{"name":"Department of Genetics, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9391-7464","authenticated-orcid":false,"given":"Peter 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