{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:36:12Z","timestamp":1788806172064,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n The restoration of uniformly distributed dystrophin protein expression is an important consideration for the development of advanced therapeutics for Duchenne muscular dystrophy (DMD).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We have generated a novel genetic mouse model (\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n ) that expresses variable and nonuniformly distributed dystrophin protein from birth as a consequence of skewed X\u2010chromosome inactivation.\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n myofibers are heterokaryons containing a mixture of myonuclei expressing either wild\u2010type or mutant dystrophin alleles in a mutually exclusive manner, resulting in dystrophin protein being spatially restricted to corresponding dystrophin\u2010expressing myonuclear domains. This phenotype models the situation in female dystrophinopathy and dystrophic muscle in which dystrophin has been incompletely restored by partially effective experimental therapeutics. Dystrophin distribution was assessed in\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n muscle sections and isolated single myofibers by immunostaining and RNA\u2010FISH analysis.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Total dystrophin expression increased by ~2.8\u2010fold (\n p<\/jats:italic>\n \u2009<\u20090.010) in aged (60\u2010week\u2010old)\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n mice relative to 6\u2010week\u2010old adults, suggestive of an aging\u2010associated accumulation of dystrophin\u2010expressing myonuclei through positive selection, although this was insufficient to resolve sarcolemmal dystrophin patchiness. Nonuniformly distributed dystrophin conferred partial protection against pathology\u2010related muscle turnover in an expression\u2010level\u2010dependent manner in both adult and aged\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n mice compared to mice expressing no dystrophin. Isolated\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n myofibers exhibited patchy \u2018zebra\u2010like\u2019 banding of dystrophin sarcolemmal coverage that colocalized with\n \u03b2<\/jats:italic>\n \u2010dystroglycan but not neuronal nitric oxide synthase, which was uniformly distributed.\n <\/jats:p>\n \n Systematic classification of isolated\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n myofibers revealed unexpected and profound differences associated with central nucleation, with dystrophin found to be absent in centrally nucleated myofibers and myofiber segments. Muscle injury alone was insufficient to recapitulate this phenomenon, suggesting that it is a feature of the dystrophic environment.\n Dmd<\/jats:italic>\n mRNA was found to be present throughout centrally nucleated segments, and proteins such as titin and F\u2010actin were uniformly distributed, suggesting that dystrophin is specifically repressed at the protein level in these regions. The microtubule network was moderately disrupted in\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n \u2018zebra\u2010banded\u2019 fibers, but this effect was not different between dystrophin\u2010positive and dystrophin\u2010negative myofiber subdomains. By contrast, centrally nucleated\n mdx52\u2010Xist<\/jats:italic>\n \u0394hs<\/jats:sup>\n myofibers exhibited severe microtubule network disruption.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n These findings reveal new insights into the importance of dystrophin spatial localization and identify a previously unappreciated barrier to effective therapeutic dystrophin restoration, particularly within regenerated or centrally nucleated myofibers.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70284","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T13:51:07Z","timestamp":1775569867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Myonuclear Domain\u2010Associated and Central Nucleation\u2010Dependent Spatial Restriction of Dystrophin Protein Expression"],"prefix":"10.1002","volume":"17","author":[{"given":"Katarzyna","family":"Chwalenia","sequence":"first","affiliation":[{"name":"Department of Paediatrics University of Oxford Oxford UK"},{"name":"Institute of Developmental and Regenerative Medicine University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivi\u2010Yun","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Paediatrics University of Oxford Oxford UK"},{"name":"Institute of Developmental and Regenerative Medicine University of Oxford Oxford UK"},{"name":"Freie Universit\u00e4t Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Hemmer","sequence":"additional","affiliation":[{"name":"Department of Paediatrics University of Oxford Oxford UK"},{"name":"Institute of Developmental and Regenerative Medicine University of Oxford Oxford UK"},{"name":"Eberhard\u2010Karls\u2010Universit\u00e4t T\u00fcbingen, Geschwister\u2010Scholl\u2010Platz T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2283-2118","authenticated-orcid":false,"given":"John\u00a0C.\u00a0W.","family":"Hildyard","sequence":"additional","affiliation":[{"name":"Comparative Neuromuscular Diseases Laboratory, Department of Clinical Science and Services Royal Veterinary College London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3578-5962","authenticated-orcid":false,"given":"Liberty\u00a0E.","family":"Roskrow","sequence":"additional","affiliation":[{"name":"Comparative Neuromuscular Diseases Laboratory, Department of Clinical Science and Services Royal Veterinary College London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4344-6438","authenticated-orcid":false,"given":"Richard\u00a0J.","family":"Piercy","sequence":"additional","affiliation":[{"name":"Comparative Neuromuscular Diseases Laboratory, Department of Clinical Science and Services Royal Veterinary College London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric\u00a0T.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, Center for NeuroGenetics, Genetics Institute University of Florida Gainesville Florida USA"},{"name":"Myology Institute University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1565-654X","authenticated-orcid":false,"given":"Annemieke","family":"Aartsma\u2010Rus","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical 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W.L.S.U2022. \u201cWave Life Sciences Provides Positive Update on Proof\u2010of\u2010Concept Study for WVE\u2010N531 in Duchenne Muscular Dystrophy \u201d GlobeNewswire News Room https:\/\/www.globenewswire.com\/news\u2010release\/2022\/12\/19\/2576214\/0\/en\/Wave\u2010Life\u2010Sciences\u2010Provides\u2010Positive\u2010Update\u2010on\u2010Proof\u2010of\u2010Concept\u2010Study\u2010for\u2010WVE\u2010N531\u2010in\u2010Duchenne\u2010Muscular\u2010Dystrophy.html."}],"container-title":["Journal of Cachexia, Sarcopenia and 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