{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:38:52Z","timestamp":1789609132089,"version":"build-2803163510"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T00:00:00Z","timestamp":1574899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"DOI":"10.3389\/fphys.2019.01436","type":"journal-article","created":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T04:14:51Z","timestamp":1574914491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":130,"title":["The Giant Protein Titin\u2019s Role in Cardiomyopathy: Genetic, Transcriptional, and Post-translational Modifications of TTN and Their Contribution to Cardiac Disease"],"prefix":"10.3389","volume":"10","author":[{"given":"Charles A.","family":"Tharp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Haywood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orfeo","family":"Sbaizero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R. G.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Mestroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.molcel.2014.08.019","article-title":"circRNA biogenesis competes with pre-mRNA splicing.","volume":"56","author":"Ashwal-Fluss","year":"2014","journal-title":"Mol. Cell."},{"key":"B2","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1161\/CIRCRESAHA.108.193326","article-title":"Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium.","volume":"104","author":"Borbely","year":"2009","journal-title":"Circ. Res."},{"key":"B3","doi-asserted-by":"crossref","first-page":"e579","DOI":"10.1161\/CIR.0000000000000455","article-title":"Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the american heart association.","volume":"134","author":"Bozkurt","year":"2016","journal-title":"Circulation"},{"key":"B4","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/j.jacc.2009.05.038","article-title":"Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy.","volume":"54","author":"Brauch","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1161\/CIRCRESAHA.116.308904","article-title":"alternative splicing of titin restores diastolic function in an HFpEF-like genetic murine model (TtnDeltaIAjxn).","volume":"119","author":"Bull","year":"2016","journal-title":"Circ. Res."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.12.012","article-title":"Force generation via beta-cardiac myosin, Titin, and alpha-actinin drives cardiac sarcomere assembly from cell-matrix adhesions.","volume":"44","author":"Chopra","year":"2018","journal-title":"Dev. Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0169007","article-title":"Titin truncating variants in dilated cardiomyopathy - prevalence and genotype-phenotype correlations.","volume":"12","author":"Franaszczyk","year":"2017","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1161\/01.res.86.11.1114","article-title":"Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity.","volume":"86","author":"Freiburg","year":"2000","journal-title":"Circ. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s10974-005-9038-1","article-title":"Titin\/connectin-based modulation of the frank-starling mechanism of the heart.","volume":"26","author":"Fukuda","year":"2005","journal-title":"J. Muscle Res. Cell Motil."},{"key":"B10","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/s00424-011-0946-1","article-title":"Cytoskeletal protein kinases: titin and its relations in mechanosensing.","volume":"462","author":"Gautel","year":"2011","journal-title":"Pflugers. Arch."},{"key":"B11","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/ng815","article-title":"Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy.","volume":"30","author":"Gerull","year":"2002","journal-title":"Nat. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1161\/CIRCGENETICS.112.962928","article-title":"Population-based variation in cardiomyopathy genes.","volume":"5","author":"Golbus","year":"2012","journal-title":"Circ. Cardiovasc. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"562","DOI":"10.15252\/emmm.201505047","article-title":"Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy.","volume":"7","author":"Gramlich","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1038\/nm.2693","article-title":"RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.","volume":"18","author":"Guo","year":"2012","journal-title":"Nat. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s12551-017-0263-9","article-title":"Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes.","volume":"9","author":"Hamdani","year":"2017","journal-title":"Biophys. Rev."},{"key":"B16","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1161\/CIRCRESAHA.111.300105","article-title":"Crucial role for Ca2(+)\/calmodulin-dependent protein kinase-II in regulating diastolic stress of normal and failing hearts via titin phosphorylation.","volume":"112","author":"Hamdani","year":"2013","journal-title":"Circ. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy.","volume":"366","author":"Herman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nrcardio.2013.105","article-title":"Dilated cardiomyopathy: the complexity of a diverse genetic architecture.","volume":"10","author":"Hershberger","year":"2013","journal-title":"Nat. Rev. Cardiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1097\/GIM.0b013e3181f2481f","article-title":"Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals.","volume":"12","author":"Hershberger","year":"2010","journal-title":"Genet. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1161\/CIRCRESAHA.109.198465","article-title":"PKC phosphorylation of titin\u2019s PEVK element: a novel and conserved pathway for modulating myocardial stiffness.","volume":"105","author":"Hidalgo","year":"2009","journal-title":"Circ. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1126\/science.aaa5458","article-title":"Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy.","volume":"349","author":"Hinson","year":"2015","journal-title":"Science"},{"key":"B22","doi-asserted-by":"publisher","first-page":"D512","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: mutations, PTMs and recalibrations.","volume":"43","author":"Hornbeck","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1016\/j.cell.2010.12.001","article-title":"A tissue-specific atlas of mouse protein phosphorylation and expression.","volume":"143","author":"Huttlin","year":"2010","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1161\/circresaha.116.309568","article-title":"RBM20 regulates circular RNA production from the titin gene.","volume":"119","author":"Khan","year":"2016","journal-title":"Circ. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1152\/physrev.00017.2009","article-title":"Muscle giants: molecular scaffolds in sarcomerogenesis.","volume":"89","author":"Kontrogianni-Konstantopoulos","year":"2009","journal-title":"Physiol. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1161\/CIRCRESAHA.108.184408","article-title":"Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs.","volume":"104","author":"Kruger","year":"2009","journal-title":"Circ. Res."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02483-3","article-title":"Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes.","volume":"9","author":"Krysiak","year":"2018","journal-title":"Nat. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1161\/circulationaha.112.139717","article-title":"Titin is a major human disease gene.","volume":"127","author":"LeWinter","year":"2013","journal-title":"Circulation"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cca.2006.06.035","article-title":"Cardiac titin: structure, functions and role in disease.","volume":"375","author":"LeWinter","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"B30","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1111\/j.1752-8062.2010.00198.x","article-title":"Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy.","volume":"3","author":"Li","year":"2010","journal-title":"Clin. Transl. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1161\/CIRCRESAHA.114.301286","article-title":"Gigantic business: titin properties and function through thick and thin.","volume":"114","author":"Linke","year":"2014","journal-title":"Circ. Res."},{"key":"B32","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. Cell Biol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1871","article-title":"Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues.","volume":"3","author":"Lundby","year":"2012","journal-title":"Nat. Commun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1161\/01.res.0000143901.37063.2f","article-title":"Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts.","volume":"95","author":"Makarenko","year":"2004","journal-title":"Circ. Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1161\/circresaha.116.309396","article-title":"Dilated cardiomyopathy: genetic determinants and mechanisms.","volume":"121","author":"McNally","year":"2017","journal-title":"Circ. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nature11928","article-title":"Circular RNAs are a large class of animal RNAs with regulatory potency.","volume":"495","author":"Memczak","year":"2013","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1111\/cts.12116","article-title":"Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy.","volume":"6","author":"Merlo","year":"2013","journal-title":"Clin. Transl. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1161\/01.cir.0000135591.37759.af","article-title":"Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy.","volume":"110","author":"Nagueh","year":"2004","journal-title":"Circulation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1007\/s00726-015-1944-y","article-title":"Chronic activation of mTOR complex 1 by branched chain amino acids and organ hypertrophy.","volume":"47","author":"Neishabouri","year":"2015","journal-title":"Amino. Acids"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1016\/j.bpj.2015.11.002","article-title":"Phosphorylating titin\u2019s cardiac N2B element by ERK2 or CaMKIIdelta lowers the single molecule and cardiac muscle force.","volume":"109","author":"Perkin","year":"2015","journal-title":"Biophys. J."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1093\/eurheartj\/ehv727","article-title":"Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases.","volume":"37","author":"Pinto","year":"2016","journal-title":"Eur. Heart J."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000716","article-title":"Protein changes contributing to right ventricular cardiomyocyte diastolic dysfunction in pulmonary arterial hypertension.","volume":"3","author":"Rain","year":"2014","journal-title":"J. Am. Heart. Assoc."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003802","article-title":"Rapamycin reverses elevated mTORC1 signaling in lamin A\/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival.","volume":"4","author":"Ramos","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"29273","DOI":"10.1074\/jbc.M112.372839","article-title":"A novel mechanism involving four-and-a-half LIM domain protein-1 and extracellular signal-regulated kinase-2 regulates titin phosphorylation and mechanics.","volume":"287","author":"Raskin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.hrthm.2011.10.016","article-title":"Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy.","volume":"9","author":"Refaat","year":"2012","journal-title":"Heart Rhythm"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3010134","article-title":"Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.","volume":"7","author":"Roberts","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/ng.3719","article-title":"Titin-truncating variants affect heart function in disease cohorts and the general population.","volume":"49","author":"Schafer","year":"2017","journal-title":"Nat. Genet."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.114.001136","article-title":"Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin.","volume":"4","author":"Schisler","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0118974","article-title":"Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.","volume":"10","author":"Shibayama","year":"2015","journal-title":"PLoS One"},{"key":"B50","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1085\/jgp.201812259","article-title":"Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance.","volume":"151","author":"Slater","year":"2019","journal-title":"J. Gen. Physiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.yjmcc.2017.09.008","article-title":"Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes.","volume":"113","author":"Streckfuss-Bomeke","year":"2017","journal-title":"J. Mol. Cell Cardiol."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-5213-9","article-title":"Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure.","volume":"19","author":"Sweet","year":"2018","journal-title":"BMC Genomics"},{"key":"B53","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s12551-017-0265-7","article-title":"Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy.","volume":"9","author":"Tabish","year":"2017","journal-title":"Biophys. Rev."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1016\/j.jacc.2017.08.063","article-title":"Phenotype and clinical outcomes of titin cardiomyopathy.","volume":"70","author":"Tayal","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1083\/jcb.140.4.853","article-title":"Titin extensibility in situ: entropic elasticity of permanently folded and permanently unfolded molecular segments.","volume":"140","author":"Trombitas","year":"1998","journal-title":"J. Cell Biol."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13675-8","article-title":"Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.","volume":"7","author":"Vikhorev","year":"2017","journal-title":"Sci. Rep."},{"key":"B57","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1038\/nrcardio.2017.190","article-title":"Role of titin in cardiomyopathy: from DNA variants to patient stratification.","volume":"15","author":"Ware","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1161\/01.res.0000021115.24712.99","article-title":"Protein kinase A phosphorylates titin\u2019s cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes.","volume":"90","author":"Yamasaki","year":"2002","journal-title":"Circ. Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.yjmcc.2015.12.022","article-title":"Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy.","volume":"91","author":"Yano","year":"2016","journal-title":"J. Mol. Cell Cardiol."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/163564","article-title":"Pressure overload by transverse aortic constriction induces maladaptive hypertrophy in a titin-truncated mouse model.","volume":"2015","author":"Zhou","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"B61","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1093\/jmcb\/mjv002","article-title":"RBM20 is an essential factor for thyroid hormone-regulated titin isoform transition.","volume":"7","author":"Zhu","year":"2015","journal-title":"J. Mol. Cell Biol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1016\/j.bbadis.2017.06.023","article-title":"Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner.","volume":"1863","author":"Zhu","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fphys.2019.01436\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T04:14:54Z","timestamp":1574914494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fphys.2019.01436\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,28]]},"references-count":62,"alternative-id":["10.3389\/fphys.2019.01436"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2019.01436","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,28]]},"article-number":"1436"}}