{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:02:20Z","timestamp":1788325340741,"version":"build-2803163510"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,5]],"date-time":"2018-01-05T00:00:00Z","timestamp":1515110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["NIGMSP20GM103432"],"award-info":[{"award-number":["NIGMSP20GM103432"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["16BGIA27790136"],"award-info":[{"award-number":["16BGIA27790136"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"USDA National Institute of Food and Agriculture","award":["1009266"],"award-info":[{"award-number":["1009266"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.<\/jats:p>","DOI":"10.3390\/genes9010018","type":"journal-article","created":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T04:21:21Z","timestamp":1515385281000},"page":"18","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-2113","authenticated-orcid":false,"given":"Maimaiti","family":"Rexiati","sequence":"first","affiliation":[{"name":"Animal Science, University of Wyoming, Laramie, WY 82071, USA"},{"name":"Center for Cardiovascular Research and integrative medicine, University of Wyoming, Laramie, WY 82071, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Sun","sequence":"additional","affiliation":[{"name":"Animal Science, University of Wyoming, Laramie, WY 82071, USA"},{"name":"Center for Cardiovascular Research and integrative medicine, University of Wyoming, Laramie, WY 82071, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Animal Science, University of Wyoming, Laramie, WY 82071, USA"},{"name":"Center for Cardiovascular Research and integrative medicine, University of Wyoming, Laramie, WY 82071, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S1097-2765(03)00270-3","article-title":"Pre-mRNA splicing: Awash in a sea of proteins","volume":"12","author":"Jurica","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0168-9525(00)02176-4","article-title":"Alternative splicing: Increasing diversity in the proteomic world","volume":"17","author":"Graveley","year":"2001","journal-title":"Trends Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1126\/science.1073774","article-title":"Predictive identification of exonic splicing enhancers in human genes","volume":"297","author":"Fairbrother","year":"2002","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1126\/science.1090100","article-title":"Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays","volume":"302","author":"Johnson","year":"2003","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1002\/bies.10394","article-title":"The spliceosome: The most complex macromolecular machine in the cell?","volume":"25","author":"Nilsen","year":"2003","journal-title":"Bioessays"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nature05304","article-title":"An RNA map predicting nova-dependent splicing regulation","volume":"444","author":"Ule","year":"2006","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1261\/rna.876308","article-title":"Splicing regulation: From a parts list of regulatory elements to an integrated splicing code","volume":"14","author":"Wang","year":"2008","journal-title":"RNA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/0168-9525(94)90233-X","article-title":"Mechanisms for selecting 5\u2032 splice sites in mammalian pre-mRNA splicing","volume":"10","author":"Horowitz","year":"1994","journal-title":"Trends Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1074\/jbc.R700031200","article-title":"Regulation of alternative splicing: More than just the abcs","volume":"283","author":"House","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrg.2015.3","article-title":"RNA mis-splicing in disease","volume":"17","author":"Scotti","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S0168-9525(01)02626-9","article-title":"Alternative splicing: Multiple control mechanisms and involvement in human disease","volume":"18","author":"Kornblihtt","year":"2002","journal-title":"Trends Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nbt964","article-title":"Alternative splicing in disease and therapy","volume":"22","author":"Baraniak","year":"2004","journal-title":"Nat. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"W252","DOI":"10.1093\/nar\/gku340","article-title":"Swiss-model: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s12265-013-9482-z","article-title":"The alternative heart: Impact of alternative splicing in heart disease","volume":"6","author":"Gatto","year":"2013","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1016\/j.bbadis.2016.11.008","article-title":"Pre-mRNA mis-splicing of sarcomeric genes in heart failure","volume":"1863","author":"Zhu","year":"2017","journal-title":"BBA Mol. Basis Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nature14508","article-title":"HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease","volume":"522","author":"Mirtschink","year":"2015","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1126\/science.280.5364.737","article-title":"Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy","volume":"280","author":"Philips","year":"1998","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","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":"ref_19","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1093\/nar\/gks1362","article-title":"Rbm20 regulates titin alternative splicing as a splicing repressor","volume":"41","author":"Li","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1172\/JCI74523","article-title":"RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mrna processing","volume":"124","author":"Maatz","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","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":"ref_22","doi-asserted-by":"crossref","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":"ref_23","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/cvr\/cvw192","article-title":"A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank\u2014Starling mechanism","volume":"112","author":"Beqqali","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.molcel.2012.05.039","article-title":"Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks","volume":"46","author":"Buljan","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.molcel.2012.05.037","article-title":"Tissue-specific alternative splicing remodels protein-protein interaction networks","volume":"46","author":"Ellis","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, K. (1985). Sarcomere-associated cytoskeletal lattices in striated muscle. Cell and Muscle Motility, Springer.","DOI":"10.1007\/978-1-4757-4723-2_10"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1126\/science.270.5234.293","article-title":"Titins: Giant proteins in charge of muscle ultrastructure and elasticity","volume":"270","author":"Labeit","year":"1995","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nrd4554","article-title":"Targeting the sarcomere to correct muscle function","volume":"14","author":"Hwang","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kong, S.W., Hu, Y.W., Ho, J.W., Ikeda, S., Polster, S., John, R., Hall, J.L., Bisping, E., Pieske, B., and Pu, W.T. (2010). Heart failure associated changes in RNA splicing of sarcomere genes. Circ. Cardiovasc. Genet.","DOI":"10.1161\/CIRCGENETICS.109.904698"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1126\/science.1088583","article-title":"A muscleblind knockout model for myotonic dystrophy","volume":"302","author":"Kanadia","year":"2003","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.molcel.2007.07.027","article-title":"Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation","volume":"28","author":"Wang","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1042\/BST0371281","article-title":"Pathogenic mechanisms of myotonic dystrophy","volume":"37","author":"Lee","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.1172\/JCI32308","article-title":"Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy","volume":"117","author":"Wang","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1093\/hmg\/ddp570","article-title":"Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1","volume":"19","author":"Koshelev","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1126\/science.1062125","article-title":"Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9","volume":"293","author":"Liquori","year":"2001","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1590\/S0066-782X2005000400011","article-title":"Myotonic dystrophy and heart disease: Behavior of arrhythmic events and conduction disturbances","volume":"84","author":"Nishioka","year":"2005","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_37","first-page":"193","article-title":"Cardiac manifestations in myotonic dystrophy type 1 patients followed using a standard protocol in a specialized unit","volume":"66","year":"2013","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/S0735-1097(85)80286-2","article-title":"Ventricular tachycardia and sudden death in myotonic dystrophy: Clinical, electrophysiologic and pathologic features","volume":"6","author":"Grigg","year":"1985","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.celrep.2013.12.025","article-title":"The MEF2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression","volume":"6","author":"Kalsotra","year":"2014","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9203","DOI":"10.1073\/pnas.0900342106","article-title":"The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing","volume":"106","author":"Warf","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.devcel.2014.08.025","article-title":"RBM24 is a major regulator of muscle-specific alternative splicing","volume":"31","author":"Yang","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1093\/cvr\/cvs095","article-title":"RNA-binding protein RBM24 is required for sarcomere assembly and heart contractility","volume":"94","author":"Poon","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1172\/JCI84015","article-title":"RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure","volume":"126","author":"Gao","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.yjmcc.2008.02.272","article-title":"Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension","volume":"44","author":"Greaser","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.yjmcc.2008.03.017","article-title":"Some rat: A very special rat with a rather special titin","volume":"44","author":"Cazorla","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1016\/j.febslet.2013.07.018","article-title":"Identification of nuclear retention domains in the RBM20 protein","volume":"587","author":"Filippello","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.yjmcc.2015.02.008","article-title":"Insights into alternative splicing of sarcomeric genes in the heart","volume":"81","author":"Weeland","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Guo, W., Bharmal, S.J., Esbona, K., and Greaser, M.L. (2010). Titin diversity\u2014Alternative splicing gone wild. BioMed Res. Int., 2010.","DOI":"10.1155\/2010\/753675"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"46351","DOI":"10.1074\/jbc.R400023200","article-title":"Properties of titin immunoglobulin and fibronectin-3 domains","volume":"279","author":"Tskhovrebova","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13385","DOI":"10.1073\/pnas.0805034105","article-title":"Mechanoenzymatics of titin kinase","volume":"105","author":"Puchner","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1152\/physrev.00017.2009","article-title":"Muscle giants: Molecular scaffolds in sarcomerogenesis","volume":"89","author":"Ackermann","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1002\/elps.200305392","article-title":"Vertical agarose gel electrophoresis and electroblotting of high-molecular-weight proteins","volume":"24","author":"Warren","year":"2003","journal-title":"Electrophoresis"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0006-3495(92)81845-3","article-title":"Passive force generation and titin isoforms in mammalian skeletal muscle","volume":"61","author":"Horowits","year":"1992","journal-title":"Biophys. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1161\/01.RES.86.1.59","article-title":"Differential expression of cardiac titin isoforms and modulation of cellular stiffness","volume":"86","author":"Cazorla","year":"2000","journal-title":"Circ. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1023\/A:1026053530766","article-title":"Gigantic variety: Expression patterns of titin isoforms in striated muscles and consequences for myofibrillar passive stiffness","volume":"24","author":"Neagoe","year":"2003","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1002\/jcb.23459","article-title":"Comprehensive analysis of titin protein isoform and alternative splicing in normal and mutant rats","volume":"113","author":"Li","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","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":"BBA Mol. Basis Dis."},{"key":"ref_58","doi-asserted-by":"crossref","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":"ref_59","doi-asserted-by":"crossref","unstructured":"Guo, W., and Sun, M. (2017). RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching. Biophys. Rev., 1\u201311.","DOI":"10.1007\/s12551-017-0267-5"},{"key":"ref_60","doi-asserted-by":"crossref","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":"Tiburcy","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3779","DOI":"10.1093\/hmg\/ddu091","article-title":"Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy","volume":"23","author":"Beraldi","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1093\/hmg\/ddv468","article-title":"Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells","volume":"25","author":"Wyles","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Guo, W., Pleitner, J.M., Saupe, K.W., and Greaser, M.L. (2013). Pathophysiological defects and transcriptional profiling in the RBM20-\/- rat model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084281"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/cts.12393","article-title":"Pharmacological modulation of calcium homeostasis in familial dilated cardiomyopathy: An in vitro analysis from an RBM20 patient-derived IPSC model","volume":"9","author":"Wyles","year":"2016","journal-title":"Clin. Transl. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","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":"ref_67","doi-asserted-by":"crossref","first-page":"e570","DOI":"10.1016\/j.ejmg.2011.07.005","article-title":"Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy","volume":"54","author":"Millat","year":"2011","journal-title":"Eur. J. Med. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","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":"ref_69","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1113\/jphysiol.2001.014381","article-title":"Cardiac titin: An adjustable multi-functional spring","volume":"541","author":"Granzier","year":"2002","journal-title":"J. Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.tcm.2012.10.005","article-title":"Tuning the molecular giant titin through phosphorylation: Role in health and disease","volume":"23","author":"Hidalgo","year":"2013","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.abb.2014.02.010","article-title":"Effect of exercise training on post-translational and post-transcriptional regulation of titin stiffness in striated muscle of wild type and IG KO mice","volume":"552","author":"Hidalgo","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1161\/CIRCULATIONAHA.113.005610","article-title":"Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole","volume":"129","author":"Methawasin","year":"2014","journal-title":"Circulation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1161\/CIRCULATIONAHA.116.023003","article-title":"Experimentally increasing the compliance of titin through RNA binding motif-20 (RBM20) inhibition improves diastolic function in a mouse model of heart failure with preserved ejection fraction","volume":"134","author":"Methawasin","year":"2016","journal-title":"Circulation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1007\/s00109-016-1483-3","article-title":"Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy","volume":"94","author":"Hinze","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","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. 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