{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:44:18Z","timestamp":1768506258899,"version":"3.49.0"},"posted":{"date-parts":[[2023,5,9]]},"group-title":"Molecular Biology","reference-count":61,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3\u2032UTR harbors a miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null\n                  <jats:italic>mdx52<\/jats:italic>\n                  mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated\n                  <jats:italic>mdx52<\/jats:italic>\n                  with body-wide miR-146a deletion (\n                  <jats:italic>146aX<\/jats:italic>\n                  ). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in\n                  <jats:italic>146aX<\/jats:italic>\n                  versus\n                  <jats:italic>mdx52<\/jats:italic>\n                  muscles; skipped dystrophin transcript levels are unchanged, suggesting a post-transcriptional mechanism-of-action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.\n                <\/jats:p>","DOI":"10.1101\/2023.05.09.540042","type":"posted-content","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T14:06:37Z","timestamp":1683727597000},"source":"Crossref","is-referenced-by-count":3,"title":["Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7454-3732","authenticated-orcid":false,"given":"Nikki M.","family":"McCormack","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey A.","family":"Calabrese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina M.","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7151-0102","authenticated-orcid":false,"given":"Christopher B.","family":"Tully","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-2068","authenticated-orcid":false,"given":"Christopher R.","family":"Heier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3458-8036","authenticated-orcid":false,"given":"Alyson A.","family":"Fiorillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023081114102352000_2023.05.09.540042v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90579-4"},{"key":"2023081114102352000_2023.05.09.540042v2.2","first-page":"54","article-title":"Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies","volume":"49","year":"1991","journal-title":"Am J Hum Genet"},{"key":"2023081114102352000_2023.05.09.540042v2.3","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.39.8.1011"},{"key":"2023081114102352000_2023.05.09.540042v2.4","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20722"},{"key":"2023081114102352000_2023.05.09.540042v2.5","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-306350"},{"key":"2023081114102352000_2023.05.09.540042v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16170-2"},{"key":"2023081114102352000_2023.05.09.540042v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.066"},{"key":"2023081114102352000_2023.05.09.540042v2.8","doi-asserted-by":"crossref","unstructured":"Heier, CR , McCormack, NM , Tully, CB , Novak, JS , Newell-Stamper, BL , Russell, AJ , et al. 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