{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T11:55:42Z","timestamp":1774007742188,"version":"3.50.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2019R1A2C2085457"],"award-info":[{"award-number":["2019R1A2C2085457"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2019R1A4A1028534"],"award-info":[{"award-number":["2019R1A4A1028534"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2021R1A2C1008058"],"award-info":[{"award-number":["2021R1A2C1008058"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2021R1A4A5032463"],"award-info":[{"award-number":["2021R1A4A5032463"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002380","name":"Hanyang University","doi-asserted-by":"publisher","award":["HY-202000000002749"],"award-info":[{"award-number":["HY-202000000002749"]}],"id":[{"id":"10.13039\/501100002380","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-18-1-0322"],"award-info":[{"award-number":["W81XWH-18-1-0322"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration due to dystrophin gene mutations. Patients with DMD initially experience muscle weakness in their limbs during adolescence. With age, patients develop fatal respiratory and cardiac dysfunctions. During the later stages of the disease, severe cardiac fibrosis occurs, compromising cardiac function. Previously, our research showed that the matricellular protein CCN5 has antifibrotic properties. Therefore, we hypothesized that CCN5 gene transfer would ameliorate cardiac fibrosis and thus improve cardiac function in DMD-induced cardiomyopathy. We utilized <jats:italic>mdx\/utrn<\/jats:italic> (\u00b1) haploinsufficient mice that recapitulated the DMD-disease phenotypes and used an adeno-associated virus serotype-9 viral vector for CCN5 gene transfer. We evaluated the onset of cardiac dysfunction using echocardiography and determined the experimental starting point in 13-month-old mice. Two months after CCN5 gene transfer, cardiac function was significantly enhanced, and cardiac fibrosis was ameliorated. Additionally, running performance was improved in CCN5 gene-transfected mice. Furthermore, <jats:italic>in silico<\/jats:italic> gene profiling analysis identified utrophin as a novel transcriptional target of CCN5. This was supplemented by a utrophin promoter assay and RNA-seq analysis, which confirmed that CCN5 was directly associated with utrophin expression. Our results showed that CCN5 may be a promising therapeutic molecule for DMD-induced cardiac and skeletal dysfunction.<\/jats:p>","DOI":"10.3389\/fcvm.2022.763544","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T02:38:23Z","timestamp":1651027103000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Matricellular Protein CCN5 Gene Transfer Ameliorates Cardiac and Skeletal Dysfunction in mdx\/utrn (\u00b1) Haploinsufficient Mice by Reducing Fibrosis and Upregulating Utrophin Expression"],"prefix":"10.3389","volume":"9","author":[{"given":"Min Ho","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimeen","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Gyun","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun","family":"Kook","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo Jin","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongtak","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1038\/s41572-021-00248-3","article-title":"Duchenne muscular dystrophy.","volume":"7","author":"Duan","year":"2021","journal-title":"Nat Rev Dis Primers."},{"key":"B2","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1016\/S0140-6736(19)32910-1","article-title":"Muscular dystrophies.","volume":"394","author":"Mercuri","year":"2019","journal-title":"Lancet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.ajpath.2018.10.010","article-title":"Fibrosis rescue improves cardiac function in Dystrophin-deficient mice and duchenne patient-specific cardiomyocytes by immunoproteasome modulation.","volume":"189","author":"Farini","year":"2019","journal-title":"Am J Pathol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2533","DOI":"10.1016\/j.jacc.2016.02.081","article-title":"Dystrophin-deficient cardiomyopathy.","volume":"67","author":"Kamdar","year":"2016","journal-title":"J Am Coll Cardiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000068446","article-title":"The heart in human dystrophinopathies.","volume":"99","author":"Finsterer","year":"2003","journal-title":"Cardiology."},{"key":"B6","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s12079-016-0324-z","article-title":"Cell surface receptors for CCN proteins.","volume":"10","author":"Lau","year":"2016","journal-title":"J Cell Commun Signal."},{"key":"B7","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1006\/excr.1999.4456","article-title":"The CCN family of angiogenic regulators: the integrin connection.","volume":"248","author":"Lau","year":"1999","journal-title":"Exp Cell Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.biocel.2008.07.025","article-title":"Functions and mechanisms of action of CCN matricellular proteins.","volume":"41","author":"Chen","year":"2009","journal-title":"Int J Biochem Cell B."},{"key":"B9","doi-asserted-by":"publisher","first-page":"4803","DOI":"10.1242\/jcs.03270","article-title":"All in the CCN family: essential matricellular signaling modulators emerge from the bunker.","volume":"119","author":"Leask","year":"2006","journal-title":"J Cell Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.yjmcc.2010.04.010","article-title":"The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis.","volume":"49","author":"Yoon","year":"2010","journal-title":"J Mol Cell Cardiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1016\/j.jacc.2016.01.030","article-title":"Matricellular protein CCN5 reverses established cardiac fibrosis.","volume":"67","author":"Jeong","year":"2016","journal-title":"J Am Coll Cardiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1517\/14712598.8.7.911","article-title":"Optimizing gene delivery vectors for the treatment of heart disease.","volume":"8","author":"Gray","year":"2008","journal-title":"Expert Opin Biol Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ymthe.2006.03.014","article-title":"Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8.","volume":"14","author":"Inagaki","year":"2006","journal-title":"Mol Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1038\/gt.2011.36","article-title":"Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction.","volume":"18","author":"Shin","year":"2011","journal-title":"Gene Ther."},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.1038\/s41536-018-0045-4","article-title":"Humanizing the mdx mouse model of DMD: the long and the short of it.","volume":"3","author":"Yucel","year":"2018","journal-title":"NPJ Regen Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/s0092-8674(00)80533-4","article-title":"Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy.","volume":"90","author":"Grady","year":"1997","journal-title":"Cell."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0117306","article-title":"Skeletal muscle fibrosis in the mdx\/utrn plus \/- mouse validates its suitability as a murine model of Duchenne muscular dystrophy.","volume":"10","author":"Gutpell","year":"2015","journal-title":"PLoS One."},{"key":"B18","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/s0092-8674(00)80532-2","article-title":"Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy.","volume":"90","author":"Deconinck","year":"1997","journal-title":"Cell."},{"key":"B19","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1002\/mus.21848","article-title":"IMPAIRED RESPIRATORY FUNCTION IN MDX AND MDX\/UTRN(+\/-) MICE.","volume":"43","author":"Huang","year":"2011","journal-title":"Muscle Nerve."},{"key":"B20","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.nmd.2011.10.011","article-title":"Comparison of skeletal muscle pathology and motor function of dystrophin and utrophin deficient mouse strains.","volume":"22","author":"van Putten","year":"2012","journal-title":"Neuromuscul Disord."},{"key":"B21","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.jns.2007.08.029","article-title":"Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice.","volume":"264","author":"Zhou","year":"2008","journal-title":"J Neurol Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/384349a0","article-title":"Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene.","volume":"384","author":"Tinsley","year":"1996","journal-title":"Nature."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1038\/4033","article-title":"Expression of full-length utrophin prevents muscular dystrophy in mdx mice.","volume":"4","author":"Tinsley","year":"1998","journal-title":"Nat Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/nm1197-1216","article-title":"Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice.","volume":"3","author":"Deconinck","year":"1997","journal-title":"Nat Med."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.2237","article-title":"Evaluation of muscle performance in mice by treadmill exhaustion test and whole-limb grip strength assay.","volume":"7","author":"Castro","year":"2017","journal-title":"Bio Protoc."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1016\/j.jacc.2006.10.078","article-title":"Myocardial delayed enhancement by magnetic resonance imaging in patients with muscular dystrophy.","volume":"49","author":"Silva","year":"2007","journal-title":"J Am Coll Cardiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1161\/CIRCRESAHA.111.259754","article-title":"Modulation of cardiac contractility by the phopholamban\/SERCA2a regulatome.","volume":"110","author":"Kranias","year":"2012","journal-title":"Circ Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"237","DOI":"10.5483\/bmbrep.2013.46.5.077","article-title":"SERCA2a: a prime target for modulation of cardiac contractility during heart failure.","volume":"46","author":"Park","year":"2013","journal-title":"BMB Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1007\/s00059-002-2354-y","article-title":"Cardiac fibrosis as a cause of diastolic dysfunction.","volume":"27","author":"Burlew","year":"2002","journal-title":"Herz."},{"key":"B30","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.jacc.2015.06.1313","article-title":"Cardiac fibrosis in patients with atrial fibrillation: mechanisms and clinical implications.","volume":"66","author":"Dzeshka","year":"2015","journal-title":"J Am Coll Cardiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1007\/s00018-013-1349-6","article-title":"The pathogenesis of cardiac fibrosis.","volume":"71","author":"Kong","year":"2014","journal-title":"Cell Mol Life Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s10741-012-9365-4","article-title":"Fibrosis and heart failure.","volume":"19","author":"Segura","year":"2014","journal-title":"Heart Fail Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1007\/s00247-013-2696-z","article-title":"Analysis of fatty infiltration and inflammation of the pelvic and thigh muscles in boys with Duchenne muscular dystrophy (DMD): grading of disease involvement on MR imaging and correlation with clinical assessments.","volume":"43","author":"Kim","year":"2013","journal-title":"Pediatr Radiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s00256-011-1240-1","article-title":"Lower leg muscle involvement in Duchenne muscular dystrophy: an MR imaging and spectroscopy study.","volume":"41","author":"Torriani","year":"2012","journal-title":"Skeletal Radiol."},{"key":"B35","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1111\/jpc.12868","article-title":"Duchenne muscular dystrophy.","volume":"51","author":"Yiu","year":"2015","journal-title":"J Paediatr Child Health."},{"key":"B36","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/ar.1092420109","article-title":"Phenotype of dystrophinopathy in old mdx mice.","volume":"242","author":"Lefaucheur","year":"1995","journal-title":"Anat Rec."},{"key":"B37","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/0022-510x(93)90027-v","article-title":"Muscular weakness in the MDX mouse.","volume":"120","author":"Muntoni","year":"1993","journal-title":"J Neurol Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/BF00687043","article-title":"Skeletal muscle pathology in X chromosome-linked muscular dystrophy (MDX) mouse.","volume":"69","author":"Tanabe","year":"1986","journal-title":"Acta Neuropathol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3791\/54052","article-title":"The treadmill fatigue test: a simple, high-throughput assay of fatigue-like behavior for the mouse.","volume":"31","author":"Dougherty","year":"2016","journal-title":"J Vis Exp."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1128\/MCB.01316-10","article-title":"CCN5, a novel transcriptional repressor of the transforming growth factor beta signaling pathway.","volume":"31","author":"Sabbah","year":"2011","journal-title":"Mol Cell Biol."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7244","article-title":"Multiplex CRISPR\/CAS9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy.","volume":"6","author":"Ousterout","year":"2015","journal-title":"Nat Commun."},{"key":"B42","article-title":"Muscle-specific CRISPR\/CAS9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy.","volume":"8","author":"Bengtsson","year":"2017","journal-title":"Nat Commun."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1038\/sj.mt.6300161","article-title":"Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression.","volume":"15","author":"Wang","year":"2007","journal-title":"Mol Ther."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1016\/j.ymthe.2018.07.011","article-title":"Systemic AAV Micro-dystrophin gene therapy for Duchenne muscular dystrophy.","volume":"26","author":"Duan","year":"2018","journal-title":"Mol Ther."},{"key":"B45","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/j.1750-3639.1996.tb00781.x","article-title":"Utrophin: a structural and functional comparison to dystrophin.","volume":"6","author":"Blake","year":"1996","journal-title":"Brain Pathol."},{"key":"B46","first-page":"209","article-title":"Utrophin upregulation in Duchenne muscular dystrophy.","volume":"24","author":"Hirst","year":"2005","journal-title":"Acta Myol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"S78","DOI":"10.1016\/s0960-8966(02)00087-1","article-title":"The role of utrophin in the potential therapy of Duchenne muscular dystrophy.","author":"Perkins","year":"2002","journal-title":"Neuromuscul Disord."},{"key":"B48","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/0960-8966(93)90111-v","article-title":"Utrophin: a potential replacement for dystrophin?","volume":"3","author":"Tinsley","year":"1993","journal-title":"Neuromuscul Disord."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-76338-1","article-title":"PMO-based let-7c site blocking oligonucleotide (SBO) mediated utrophin upregulation in mdx mice, a therapeutic approach for Duchenne muscular dystrophy (DMD).","volume":"10","author":"Sengupta","year":"2020","journal-title":"Sci Rep."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019189","article-title":"Daily treatment with SMTC1100, a novel small molecule utrophin upregulator, dramatically reduces the dystrophic symptoms in the MDX mouse.","volume":"6","author":"Tinsley","year":"2011","journal-title":"PLoS One."},{"key":"B51","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.molmed.2007.10.003","article-title":"New therapies for Duchenne muscular dystrophy: challenges, prospects and clinical trials.","volume":"13","author":"Cossu","year":"2007","journal-title":"Trends Mol Med."},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1016\/j.nmd.2017.06.443","article-title":"PhaseOut DMD: a Phase 2, proof of concept, clinical study of utrophin modulation with ezutromid.","volume":"27","author":"Muntoni","year":"2017","journal-title":"Neuromuscular Disord."},{"key":"B53","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-4939-7374-3_1","article-title":"An overview of recent therapeutics advances for Duchenne Muscular dystrophy.","volume":"1687","author":"Mah","year":"2018","journal-title":"Methods Mol Biol."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-4-7","article-title":"Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne muscular dystrophy.","volume":"4","author":"Pessina","year":"2014","journal-title":"Skelet Muscle."},{"key":"B55","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1002\/mus.21869","article-title":"Prevention of muscle fibrosis and myonecrosis in mdx mice by suramin, a TGF-beta1 blocker.","volume":"43","author":"Taniguti","year":"2011","journal-title":"Muscle Nerve."},{"key":"B56","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1097\/NEN.0b013e3181e9a34b","article-title":"Targeting fibrosis in Duchenne muscular dystrophy.","volume":"69","author":"Zhou","year":"2010","journal-title":"J Neuropathol Exp Neurol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nature13073","article-title":"Inhibition of miR-25 improves cardiac contractility in the failing heart.","volume":"508","author":"Wahlquist","year":"2014","journal-title":"Nature."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.763544\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T02:38:30Z","timestamp":1651027110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.763544\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,26]]},"references-count":57,"alternative-id":["10.3389\/fcvm.2022.763544"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2022.763544","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,26]]},"article-number":"763544"}}