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We previously showed that the exercise\u2010induced long noncoding RNA CYTOR promotes fast\u2010twitch myogenesis. Here, we identify an independent functional element within human CYTOR, and optimize its RNA delivery. In human primary myoblasts exogenous CYTOR exon 2 recapitulates the effect of full\u2010length CYTOR by boosting fast\u2010twitch myogenic differentiation. Furthermore, chemically modified CYTOR exon 2 RNA\n                    <jats:sup>\u03a8U<\/jats:sup>\n                    (N1\u2010me\u2010PseudoU, 7\u2010methyl guanosine 5\u2032Cap, polyA) enhances RNA stability and reduces immunogenicity\u00a0to CYTOR\n                    <jats:sup>exon2<\/jats:sup>\n                    RNA. Viral\u2010 or chemically optimized RNA\u2010mediated CYTOR\n                    <jats:sup>exon2<\/jats:sup>\n                    administration drives commitment toward myogenic maturation in Duchenne muscular dystrophy\u2010derived primary myoblasts, myogenic progenitor cells, and mouse embryonic stem cells. Furthermore, CYTOR\n                    <jats:sup>exon2, m1\u03a8U<\/jats:sup>\n                    improves key disease characteristics in dystrophic myotubes, including calcium handling and mitochondrial bioenergetics. In summary, we identify CYTOR exon 2 as the functional domain of CYTOR that can be delivered in a disease context using chemical modifications. This is of particular importance given the susceptibility of fast muscle fibers in different muscle pathologies such as aging and dystrophies, and the oncogenic effect of CYTOR exon 1. This study, therefore, highlights the potential of identifying functional domains in noncoding RNAs. Delivery, or targeting of RNA domains might constitute next\u2010generation RNA therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/advs.202410908","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T09:19:46Z","timestamp":1739783986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Delivery of A Chemically Modified Noncoding RNA Domain Improves Dystrophic Myotube Function"],"prefix":"10.1002","volume":"12","author":[{"given":"Zeinabou","family":"Niasse\u2010Sy","sequence":"first","affiliation":[{"name":"Laboratory of Integrative Systems Physiology \u00c9cole polytechnique f\u00e9d\u00e9rale de Lausanne (EPFL)  Lausanne 1015 Switzerland"},{"name":"Universit\u00e9 Lyon Facult\u00e9 de M\u00e9decine et de Ma\u00efeutique Lyon\u2010Sud Charles Merieux  Oullins 69007 France"},{"name":"Hospices Civils de Lyon Groupement Hospitalier Sud Service de G\u00e9riatrie  Lyon 69002 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