{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:16:24Z","timestamp":1790813784271,"version":"4.1.0"},"reference-count":73,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T00:00:00Z","timestamp":1591142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2020R1A2C1005161"],"award-info":[{"award-number":["2020R1A2C1005161"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2017M3A9D8048708"],"award-info":[{"award-number":["2017M3A9D8048708"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2013M3A9B6076413"],"award-info":[{"award-number":["2013M3A9B6076413"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2020,10]]},"abstract":"Abstract<\/jats:title>Background<\/jats:title>The microRNAs (miRNAs) down\u2010regulated in aged mouse skeletal muscle were mainly clustered within the delta\u2010like homologue 1 and the type III iodothyronine deiodinase (Dlk1\u2010Dio3<\/jats:italic>) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1\u2010Dio3<\/jats:italic> cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age\u2010related muscle atrophy.<\/jats:p><\/jats:sec>Methods<\/jats:title>To examine anti\u2010atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3\u2032 untranslated region (UTR) and RNA pull\u2010down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo<\/jats:italic>, we generated adeno\u2010associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9\u2010GFP) bearing miR\u2010376c\u20103p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo<\/jats:italic> isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80\u00a0years) were used to investigate expression levels of the conserved miRNAs in the Dlk1\u2010Dio3<\/jats:italic> cluster.<\/jats:p><\/jats:sec>Results<\/jats:title>We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti\u2010atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3\u2032 UTR of muscle atrophy gene\u20101 (Atrogin\u20101<\/jats:italic>) encoding a muscle\u2010specific E3 ligase. Direct interactions were identified between these miRNAs and the 3\u2032 UTR of Atrogin\u20101<\/jats:italic>, leading to repression of Atrogin\u20101 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR\u2010376c\u20103p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down\u2010regulated in human muscle from individuals\u00a0>\u00a050\u00a0years old.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our study suggests that genetic intervention using a muscle\u2010directed miRNA delivery system has therapeutic efficacy in preventing Atrogin\u20101\u2010mediated muscle atrophy in sarcopenia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12578","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T02:11:08Z","timestamp":1591236668000},"page":"1336-1350","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["A subset of microRNAs in the Dlk1\u2010Dio3<\/i> cluster regulates age\u2010associated muscle atrophy by targeting Atrogin\u20101<\/i>"],"prefix":"10.1002","volume":"11","author":[{"given":"Yeo Jin","family":"Shin","sequence":"first","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u2010Soo","family":"Kwon","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung\u2010Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon\u2010Kyu","family":"Kim","sequence":"additional","affiliation":[{"name":"Personalized Genomic Medicine Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon 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Sook","family":"Kang","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"},{"name":"Department of Functional Genomics, KRIBB School of Bioscience Korea University of Science and Technology (UST) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju Yeon","family":"Kwak","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Hoon","family":"Son","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Yi","family":"Choi","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Ryul","family":"Yang","sequence":"additional","affiliation":[{"name":"Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seokho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicinal Biotechnology, College of Health Sciences Dong\u2010A University Busan Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon\u2010Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of New Drug Discovery and Development Chungnam National University Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hak C.","family":"Jang","sequence":"additional","affiliation":[{"name":"Internal Medicine Seoul National University Bundang Hospital Gyeonggi\u2010do 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