{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:07:05Z","timestamp":1790842025900,"version":"4.1.0"},"reference-count":48,"publisher":"SAGE Publications","issue":"9-10","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by dystrophin deficiency. Dystrophin consists of the amino terminus, central rod domain with 24 spectrin-like repeats and four hinges (H), cysteine-rich domain, and carboxyl terminus. Several highly abbreviated micro-dystrophins (\u03bcDys) are currently in clinical trials. They all carry H1 and H4. In this study, we investigated whether these two hinges are essential for \u03bcDy function in murine DMD models. Three otherwise identical \u03bcDys were engineered to contain H1 and\/or H4 and were named H1\/H4 (with both H1 and H4), \u0394H1 (without H1), and \u0394H4 (without H4). These constructs were packaged in adeno-associated virus serotype-9 and delivered to the tibialis anterior muscle of 3-month-old male mdx4cv mice (1E12 vector genome particles\/muscle). Three months later, we detected equivalent \u03bcDys expression in total muscle lysate. However, only H1\/H4 and \u0394H1 showed correct sarcolemmal localization. \u0394H4 mainly existed as sarcoplasmic aggregates. H1\/H4 and \u0394H1, but not \u0394H4, fully restored the dystrophin-associated protein complex and significantly improved the specific muscle force. Eccentric contraction-induced force decline was best protected by H1\/H4, followed by \u0394H1, but not by \u0394H4. Next, we compared H1\/H4 and \u0394H1 in 6-week-old male mdx mice by intravenous injection (1E13 vector genome particles\/mouse). Four months postinjection, H1\/H4 significantly outperformed \u0394H1 in extensor digitorum longus muscle force measurements but two constructs yielded comparable electrocardiography improvements. We conclude that H4 is essential for \u03bcDys function and H1 facilitates force production. Our findings will help develop next-generation \u03bcDys gene therapy.<\/jats:p>","DOI":"10.1089\/hum.2022.180","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T03:03:12Z","timestamp":1667185392000},"page":"459-470","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":19,"title":["The Implication of Hinge 1 and Hinge 4 in Micro-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy"],"prefix":"10.1177","volume":"34","author":[{"given":"Lakmini P.","family":"Wasala","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais B.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nalinda B.","family":"Wasala","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, College of Engineering, The University of Missouri, Columbia, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4109-1132","authenticated-orcid":false,"given":"Dongsheng","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, The University of Missouri, Columbia, Missouri, USA."},{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."},{"name":"Department of Chemical and Biomedical Engineering, College of Engineering, The University of Missouri, Columbia, Missouri, USA."},{"name":"Department of Neurology, School of Medicine, The University of Missouri, Columbia, Missouri, USA."},{"name":"Department of Biomedical Sciences, College of Veterinary Medicine; 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