{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T07:57:47Z","timestamp":1773388667083,"version":"3.50.1"},"reference-count":75,"publisher":"The Company of Biologists","issue":"18","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"crossref","award":["13CVD04"],"award-info":[{"award-number":["13CVD04"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["MSCA-RISE-2014"],"award-info":[{"award-number":["MSCA-RISE-2014"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["H2020 Marie Sk\u0142odowska-Curie Actions"],"award-info":[{"award-number":["H2020 Marie Sk\u0142odowska-Curie Actions"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R35HL144998"],"award-info":[{"award-number":["R35HL144998"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Titin is a giant sarcomeric protein that is involved in a large number of functions, with a primary role in skeletal and cardiac sarcomere organization and stiffness. The titin gene (TTN) is subject to various alternative splicing events, but in the region that is present at the M-line, the only exon that can be spliced out is Mex5, which encodes for the insertion sequence 7 (is7). Interestingly, in the heart, the majority of titin isoforms are Mex5+, suggesting a cardiac role for is7. Here, we performed comprehensive functional, histological, transcriptomic, microscopic and molecular analyses of a mouse model lacking the Ttn Mex5 exon (\u0394Mex5), and revealed that the absence of the is7 is causative for dilated cardiomyopathy. \u0394Mex5 mice showed altered cardiac function accompanied by increased fibrosis and ultrastructural alterations. Abnormal expression of excitation\u2013contraction coupling proteins was also observed. The results reported here confirm the importance of the C-terminal region of titin in cardiac function and are the first to suggest a possible relationship between the is7 and excitation\u2013contraction coupling. Finally, these findings give important insights for the identification of new targets in the treatment of titinopathies.<\/jats:p>","DOI":"10.1242\/jcs.258684","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T08:45:52Z","timestamp":1629189952000},"source":"Crossref","is-referenced-by-count":6,"title":["Titin M-line insertion sequence 7 is required for proper cardiac function in mice"],"prefix":"10.1242","volume":"134","author":[{"given":"Ariane","family":"Biquand","sequence":"first","affiliation":[{"name":"Genethon, 91000 Evry, France"},{"name":"Universit\u00e9 Paris-Saclay, Univ Evry, Inserm, G\u00e9n\u00e9thon, Integrare research unit UMR_S951, 91000 Evry-Courcouronnes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8593-5558","authenticated-orcid":false,"given":"Simone","family":"Spinozzi","sequence":"additional","affiliation":[{"name":"Genethon, 91000 Evry, France"},{"name":"Universit\u00e9 Paris-Saclay, Univ Evry, Inserm, G\u00e9n\u00e9thon, Integrare research unit UMR_S951, 91000 Evry-Courcouronnes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Tonino","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e9r\u00e9mie","family":"Cosette","sequence":"additional","affiliation":[{"name":"Genethon, 91000 Evry, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Strom","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaher","family":"Elbeck","sequence":"additional","affiliation":[{"name":"Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Heart and Vascular Theme, Karolinska Institutet, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph","family":"Kn\u00f6ll","sequence":"additional","affiliation":[{"name":"Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Heart and Vascular Theme, Karolinska Institutet, 141 57 Huddinge, Sweden"},{"name":"Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henk","family":"Granzier","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Lostal","sequence":"additional","affiliation":[{"name":"Genethon, 91000 Evry, France"},{"name":"Universit\u00e9 Paris-Saclay, Univ Evry, Inserm, G\u00e9n\u00e9thon, Integrare research unit UMR_S951, 91000 Evry-Courcouronnes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-446X","authenticated-orcid":false,"given":"Isabelle","family":"Richard","sequence":"additional","affiliation":[{"name":"Genethon, 91000 Evry, France"},{"name":"Universit\u00e9 Paris-Saclay, Univ Evry, Inserm, G\u00e9n\u00e9thon, Integrare research unit UMR_S951, 91000 Evry-Courcouronnes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2021,9,17]]},"reference":[{"key":"2021091708465643200_JCS258684C1","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1161\/hh2301.100981","article-title":"The complete gene sequence of titin, expression of an unusual \u2248700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system","volume":"89","author":"Bang","year":"2001","journal-title":"Circ. Res."},{"key":"2021091708465643200_JCS258684C2","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.jmb.2014.12.017","article-title":"Titin and obscurin: giants holding hands and discovery of a new Ig domain subset","volume":"427","author":"Benian","year":"2015","journal-title":"J. Mol. Biol."},{"key":"2021091708465643200_JCS258684C3","doi-asserted-by":"publisher","first-page":"10450","DOI":"10.1074\/jbc.M312664200","article-title":"Myospryn is a novel binding partner for dysbindin in muscle","volume":"279","author":"Benson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021091708465643200_JCS258684C4","doi-asserted-by":"publisher","first-page":"6312","DOI":"10.1038\/s41598-017-06395-6","article-title":"Ryanodine receptors are part of the myospryn complex in cardiac muscle","volume":"7","author":"Benson","year":"2017","journal-title":"Sci. Rep."},{"key":"2021091708465643200_JCS258684C5","doi-asserted-by":"publisher","first-page":"140041","DOI":"10.1098\/rsob.140041","article-title":"Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line","volume":"4","author":"Bogomolovas","year":"2014","journal-title":"Open Biol."},{"key":"2021091708465643200_JCS258684C6","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1002\/ana.21089","article-title":"C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy","volume":"61","author":"Carmignac","year":"2007","journal-title":"Ann. Neurol."},{"key":"2021091708465643200_JCS258684C7","doi-asserted-by":"publisher","first-page":"4608","DOI":"10.1093\/hmg\/ddq388","article-title":"Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies","volume":"19","author":"Charton","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021091708465643200_JCS258684C8","doi-asserted-by":"publisher","first-page":"3718","DOI":"10.1093\/hmg\/ddv116","article-title":"CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy","volume":"24","author":"Charton","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2021091708465643200_JCS258684C9","first-page":"4518","article-title":"Exploiting the CRISPR\/Cas9 system to study alternative splicing in vivo: application to titin","volume":"25","author":"Charton","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2021091708465643200_JCS258684C10","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1002\/humu.22611","article-title":"A rising titan: TTN review and mutation update","volume":"35","author":"Chauveau","year":"2014","journal-title":"Hum. 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Disord."},{"key":"2021091708465643200_JCS258684C72","doi-asserted-by":"publisher","first-page":"140","DOI":"10.3389\/fcvm.2019.00140","article-title":"The Role of the TGF-\u03b2 Superfamily in Myocardial Infarction","volume":"6","author":"Hanna","year":"2019","journal-title":"Front. Cardiovasc. Med."},{"key":"2021091708465643200_JCS258684C73","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1161\/CIRCULATIONAHA.104.516963","article-title":"Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart","volume":"112","author":"Heymans","year":"2005","journal-title":"Circulation"},{"key":"2021091708465643200_JCS258684C24","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.cardiores.2005.06.013","article-title":"Expression and regulation of the atrial natriuretic factor encoding gene Nppa during development and disease","volume":"67","author":"Houweling","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"2021091708465643200_JCS258684C25","doi-asserted-by":"publisher","first-page":"714197","DOI":"10.1155\/2015\/714197","article-title":"The sarcomeric M-region: a molecular command center for diverse cellular processes","volume":"2015","author":"Hu","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"2021091708465643200_JCS258684C26","doi-asserted-by":"publisher","first-page":"e1603081","DOI":"10.1126\/sciadv.1603081","article-title":"Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin","volume":"3","author":"Hu","year":"2017","journal-title":"Sci. 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Cell Sci."},{"key":"2021091708465643200_JCS258684C33","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.1242\/jcs.046193","article-title":"Obscurin determines the architecture of the longitudinal sarcoplasmic reticulum","volume":"122","author":"Lange","year":"2009","journal-title":"J. Cell Sci."},{"key":"2021091708465643200_JCS258684C34","doi-asserted-by":"crossref","first-page":"118440","DOI":"10.1016\/j.bbamcr.2019.02.003","article-title":"The M-band: the underestimated part of the sarcomere","volume":"1867","author":"Lange","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"2021091708465643200_JCS258684C35","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1083\/jcb.146.3.631","article-title":"I-band titin in cardiac muscle is a three-element molecular spring and is critical for maintaining thin filament structure","volume":"146","author":"Linke","year":"1999","journal-title":"J. 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Cell Sci."},{"key":"2021091708465643200_JCS258684C46","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1291\/hypres.30.1239","article-title":"Gene polymorphism of myospryn (cardiomyopathy-associated 5) is associated with left ventricular wall thickness in patients with hypertension","volume":"30","author":"Nakagami","year":"2007","journal-title":"Hypertens. Res."},{"key":"2021091708465643200_JCS258684C47","doi-asserted-by":"publisher","first-page":"312a","DOI":"10.1016\/j.bpj.2017.11.1765","article-title":"A novel mouse model for titin-based dilated cardiomyopathy","volume":"114","author":"Nusayr","year":"2018","journal-title":"Biophys. J."},{"key":"2021091708465643200_JCS258684C48","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1007\/BF00121071","article-title":"M-band structure, M-bridge interactions and contraction speed in vertebrate cardiac muscles","volume":"15","author":"Pask","year":"1994","journal-title":"J. Muscle Res. 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