{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:30:47Z","timestamp":1790800247761,"version":"4.1.0"},"reference-count":70,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient\u2019s myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations.<\/jats:p>","DOI":"10.3390\/ijms22179625","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T21:47:38Z","timestamp":1630964858000},"page":"9625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents"],"prefix":"10.3390","volume":"22","author":[{"given":"Roua","family":"Hassoun","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Budde","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Georg","family":"Mannherz","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Anatomy and Molecular Embryology, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6533-770X","authenticated-orcid":false,"given":"M\u00e1ria","family":"L\u00f3di","sequence":"additional","affiliation":[{"name":"Department of Neuroanatomy and Molecular Brain Research, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Setsuko","family":"Fujita-Becker","sequence":"additional","affiliation":[{"name":"Cryoelectron Microscopy, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai Thorsten","family":"Laser","sequence":"additional","affiliation":[{"name":"Centre for Congenital Heart Disease\/Pediatric Cardiology, Heart and Diabetes Centre NRW, University Clinic of the Ruhr University Bochum, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-7693","authenticated-orcid":false,"given":"Anna","family":"G\u00e4rtner","sequence":"additional","affiliation":[{"name":"Heart and Diabetes Centre NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr University Bochum, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-2498","authenticated-orcid":false,"given":"Karin","family":"Klingel","sequence":"additional","affiliation":[{"name":"Institute for Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e9e","family":"M\u00f6hner","sequence":"additional","affiliation":[{"name":"Institute of Vegetative Physiology, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Stehle","sequence":"additional","affiliation":[{"name":"Institute of Vegetative Physiology, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Innas","family":"Sultana","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9297-4926","authenticated-orcid":false,"given":"Thomas","family":"Schaaf","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Majchrzak","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Krause","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry I, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc M.","family":"Nowaczyk","sequence":"additional","affiliation":[{"name":"Plant Biochemistry, Faculty of Biology and Biotechnology, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"M\u00fcgge","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Pfitzer","sequence":"additional","affiliation":[{"name":"Institute of Vegetative Physiology, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus R.","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Cryoelectron Microscopy, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazha","family":"Hamdani","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Milting","sequence":"additional","affiliation":[{"name":"Heart and Diabetes Centre NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr University Bochum, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelia","family":"Jaquet","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0527-1526","authenticated-orcid":false,"given":"Diana","family":"Cimiotti","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany"},{"name":"Department of Clinical Pharmacology, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1161\/CIRCRESAHA.116.309386","article-title":"Pediatric Cardiomyopathies","volume":"121","author":"Lee","year":"2017","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cimiotti, D., Budde, H., Hassoun, R., and Jaquet, K. (2021). Genetic restrictive cardiomyopathy: Causes and consequences\u2014an integrative approach. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020558"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1161\/CIRCULATIONAHA.112.104638","article-title":"Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: A report from the Pediatric Cardiomyopathy Registry","volume":"126","author":"Webber","year":"2012","journal-title":"Circulation"},{"key":"ref_4","unstructured":"Botto, L.D. (2004, September 01). Left Ventricular Non-Compaction: Orphanet Encyclopedia. Available online: https:\/\/www.orpha.net\/data\/patho\/GB\/uk-LVNC.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1017\/S1047951115000943","article-title":"Lessons learned from the Pediatric Cardiomyopathy Registry (PCMR) Study Group","volume":"25","author":"Wilkinson","year":"2015","journal-title":"Cardiol. Young"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1056\/NEJMoa021715","article-title":"The incidence of pediatric cardiomyopathy in two regions of the United States","volume":"348","author":"Lipshultz","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1001\/jama.296.15.1867","article-title":"Incidence, causes, and outcomes of dilated cardiomyopathy in children","volume":"296","author":"Towbin","year":"2006","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.yjmcc.2008.03.025","article-title":"Protein quality control and degradation in cardiomyocytes","volume":"45","author":"Wang","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dorsch, L.M., Schuldt, M., dos Remedios, C.G., Schinkel, A.F.L., de Jong, P.L., Michels, M., Kuster, D.W.D., Brundel, B.J.J.M., and van der Velden, J. (2019). Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy. Cells, 8.","DOI":"10.3390\/cells8070741"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/nrcardio.2017.89","article-title":"Proteostasis in cardiac health and disease","volume":"14","author":"Henning","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/cvr\/cvq009","article-title":"Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation","volume":"86","author":"Luedde","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s10974-020-09592-5","article-title":"A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C","volume":"42","author":"Reinoso","year":"2020","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev.physiol.67.040403.114025","article-title":"Calcium, thin filaments, and the integrative biology of cardiac contractility","volume":"67","author":"Kobayashi","year":"2005","journal-title":"Annu. Rev. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1007\/s00239-009-9202-0","article-title":"To Investigate Protein Evolution by Detecting Suppressed Epitope Structures","volume":"68","author":"Chong","year":"2009","journal-title":"J. Mol. Evol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.jmb.2004.04.046","article-title":"Switching of troponin I: Ca(2+) and myosin-induced activation of heart muscle","volume":"340","author":"Robinson","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7405","DOI":"10.1021\/bi200506k","article-title":"A model of calcium activation of the cardiac thin filament","volume":"50","author":"Manning","year":"2011","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.abb.2016.03.011","article-title":"Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C","volume":"601","author":"Zot","year":"2016","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nature01780","article-title":"Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form","volume":"424","author":"Takeda","year":"2003","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1023\/B:MCBI.0000049141.37823.19","article-title":"The contractile apparatus as a target for drugs against heart failure: Interaction of levosimendan, a calcium sensitiser, with cardiac troponin c","volume":"266","author":"Sorsa","year":"2004","journal-title":"Mol. Cell. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1111\/j.1476-5381.2010.00942.x","article-title":"Biological actions of green tea catechins on cardiac troponin C","volume":"161","author":"Tadano","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23012","DOI":"10.1074\/jbc.M109.021352","article-title":"Solution structure of human cardiac troponin C in complex with the green tea polyphenol, (-)-epigallocatechin 3-gallate","volume":"284","author":"Robertson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Cimiotti, D., Fujita-Becker, S., M\u00f6hner, D., Smolina, N., Budde, H., Wies, A., Morgenstern, L., Gudkova, A., Sejersen, T., and Sj\u00f6berg, G. (2020). Infantile restrictive cardiomyopathy: cTnI-R170G\/W impair the interplay of sarcomeric proteins and the integrity of thin filaments. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229227"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1074\/jbc.M110.170605","article-title":"Myosin binding protein C interaction with actin: Characterization and mapping of the binding site","volume":"286","author":"Rybakova","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1083\/jcb.201306077","article-title":"Human myocytes are protected from titin aggregation-induced stiffening by small heat shock proteins","volume":"204","author":"Unger","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"240","DOI":"10.3389\/fphys.2020.00240","article-title":"Modulation of Titin-Based Stiffness in Hypertrophic Cardiomyopathy via Protein Kinase D","volume":"11","author":"Herwig","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","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":"ref_27","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cardfail.2005.07.006","article-title":"Proteomic analysis reveals significant alternations of cardiac small heat shock protein expression in congestive heart failure","volume":"12","author":"Dohke","year":"2006","journal-title":"J. Card. Fail."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e003699","DOI":"10.1161\/JAHA.116.003699","article-title":"Postnatal Development of Right Ventricular Myofibrillar Biomechanics in Relation to the Sarcomeric Protein Phenotype in Pediatric Patients with Conotruncal Heart Defects","volume":"5","author":"Elhamine","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13395-015-0037-7","article-title":"Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene","volume":"5","author":"Joureau","year":"2015","journal-title":"Skelet. Muscle"},{"key":"ref_30","unstructured":"Tadano, N., Morimoto, S., and Sasaguri, T. (2005, January 25\u201328). EGCg, a major polyphenol in green tea, binds to cardiac troponin C and desensitizes cardiac muscle contraction to Ca2+. Proceedings of the International Symposium Celebrating 40th Anniversary of Troponin Discovery, 33rd NIPS Conference, Okazaki, Japan."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0006-3495(93)81110-X","article-title":"Regulation of the interaction between actin and myosin subfragment 1: Evidence for three states of the thin filament","volume":"65","author":"McKillop","year":"1993","journal-title":"Biophys. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"H2344","DOI":"10.1152\/ajpheart.00541.2006","article-title":"Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure","volume":"291","author":"Belin","year":"2006","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"468","DOI":"10.3389\/fphys.2020.00468","article-title":"Regulation of Myofilament Contractile Function in Human Donor and Failing Hearts","volume":"11","author":"McDonald","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"H1221","DOI":"10.1152\/ajpheart.00409.2019","article-title":"Increased myocyte calcium sensitivity in end-stage pediatric dilated cardiomyopathy","volume":"317","author":"Nakano","year":"2019","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1016\/j.jacc.2018.08.2171","article-title":"Genetic Basis of Severe Childhood-Onset Cardiomyopathies","volume":"72","author":"Vasilescu","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/humu.1143","article-title":"First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy","volume":"17","author":"Hoffmann","year":"2001","journal-title":"Hum. Mutat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31845","DOI":"10.1074\/jbc.M112.377713","article-title":"A Mutation in TNNC1-encoded Cardiac Troponin C, TNNC1-A31S, Predisposes to Hypertrophic Cardiomyopathy and Ventricular Fibrillation","volume":"287","author":"Parvatiyar","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.yjmcc.2015.08.017","article-title":"The structural and functional effects of the familial hypertrophic cardiomyopathy-linked cardiac troponin C mutation, L29Q","volume":"87","author":"Robertson","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6087","DOI":"10.1111\/j.1742-4658.2005.05001.x","article-title":"Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C","volume":"272","author":"Schmidtmann","year":"2005","journal-title":"FEBS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1203\/01.pdr.0000233004.95404.1f","article-title":"Development and Cardiac Contractility: Cardiac Troponin T Isoforms and Cytosolic Calcium in Rabbit","volume":"60","author":"McCall","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fmolb.2019.00068","article-title":"Computational Studies of Cardiac and Skeletal Troponin","volume":"6","author":"Bowman","year":"2019","journal-title":"Front. Mol. Biosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20054","DOI":"10.1074\/jbc.RA119.011177","article-title":"The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation","volume":"294","author":"Johnston","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0008-6363(01)00354-6","article-title":"Heat shock proteins and cardiac protection","volume":"51","author":"Latchman","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5342","DOI":"10.1038\/s41467-018-07718-5","article-title":"Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks","volume":"9","author":"Freilich","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s12192-012-0371-1","article-title":"The small heat shock proteins \u03b1B-crystallin and Hsp27 suppress SOD1 aggregation in vitro","volume":"18","author":"Yerbury","year":"2013","journal-title":"Cell Stress Chaperones"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jchf.2015.10.007","article-title":"Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction","volume":"4","author":"Franssen","year":"2016","journal-title":"JACC Heart Fail."},{"key":"ref_47","first-page":"390","article-title":"Protein quality control in protection against systolic overload cardiomyopathy: The long term role of small heat shock proteins","volume":"2","author":"Kumarapeli","year":"2010","journal-title":"Am. J. Transl. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ijcard.2011.07.022","article-title":"Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan","volume":"159","author":"Papp","year":"2012","journal-title":"Int. J. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1161\/CIRCULATIONAHA.106.668640","article-title":"Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction","volume":"115","author":"Givertz","year":"2007","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jep.2017.08.035","article-title":"Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases","volume":"210","author":"Eng","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1002\/humu.24096","article-title":"Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20","volume":"41","author":"Gaertner","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Klauke, B., Gaertner-Rommel, A., Schulz, U., Kassner, A., zu Knyphausen, E., Laser, T., Kececioglu, D., Paluszkiewicz, L., Blanz, U., and Sandica, E. (2017). High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189489"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15469","DOI":"10.1016\/S0021-9258(19)49558-6","article-title":"Determination of residue specificity in the EF-hand of troponin C for Ca2+ coordination, by genetic engineering","volume":"267","author":"Babu","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1046\/j.1432-1327.1999.00261.x","article-title":"Characterization of the cardiac holotroponin complex reconstituted from native cardiac troponin T and recombinant I and C","volume":"261","author":"Reiffert","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"14593","DOI":"10.1021\/bi0115232","article-title":"Effects of phosphorylation and mutation R145G on human cardiac troponin I function","volume":"40","author":"Deng","year":"2001","journal-title":"Biochemistry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/j.1432-1033.1980.tb04437.x","article-title":"The interaction of bovine pancreatic deoxyribonuclease I and skeletal muscle actin","volume":"104","author":"Mannherz","year":"1980","journal-title":"Eur. J. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1042\/bj0430271","article-title":"Tropomyosin: A new asymmetric protein component of the muscle fibril","volume":"43","author":"Bailey","year":"1948","journal-title":"Biochem. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0022-2836(69)90483-5","article-title":"Substructure of the myosin molecule. I. Subfragments of myosin by enzymic degradation","volume":"42","author":"Lowey","year":"1969","journal-title":"J. Mol. Biol."},{"key":"ref_60","first-page":"205","article-title":"Both isoforms of skeletal muscle subfragment 1 (S1A1 and S1A2) can induce actin polymerization with equal speed in the absence of ATP","volume":"62","author":"Schick","year":"1993","journal-title":"Eur. J. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","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":"ref_62","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10974-010-9231-8","article-title":"More severe cellular phenotype in human idiopathic dilated cardiomyopathy compared to ischemic heart disease","volume":"31","author":"Hamdani","year":"2010","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11296","DOI":"10.1016\/S0021-9258(19)70290-7","article-title":"The excimer fluorescence of pyrene-labeled tropomyosin. A probe of conformational dynamics","volume":"255","author":"Graceffa","year":"1980","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1432-1033.1975.tb20981.x","article-title":"Depolymerisation of F-actin to G-actin and its repolymerisation in the presence of analogs of adenosine triphosphate","volume":"60","author":"Mannherz","year":"1975","journal-title":"Eur. J. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ab.2003.10.047","article-title":"Visible fluorescent detection of proteins in polyacrylamide gels without staining","volume":"326","author":"Ladner","year":"2004","journal-title":"Anal. Biochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3389\/fphys.2017.00221","article-title":"Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation","volume":"8","author":"Veltri","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41467-017-02762-z","article-title":"Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo","volume":"9","author":"Gilsbach","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1164680","article-title":"Evidence for cardiomyocyte renewal in humans","volume":"324","author":"Bergmann","year":"2009","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.diff.2011.10.002","article-title":"Nuclear cardiac troponin and tropomyosin are expressed early in cardiac differentiation of rat mesenchymal stem cells","volume":"83","author":"Asumda","year":"2012","journal-title":"Differentiation"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"359","DOI":"10.3389\/fphys.2018.00359","article-title":"Burst-Like Transcription of Mutant and Wildtype MYH7-Alleles as Possible Origin of Cell-to-Cell Contractile Imbalance in Hypertrophic Cardiomyopathy","volume":"9","author":"Montag","year":"2018","journal-title":"Front. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:57:03Z","timestamp":1760165823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,6]]},"references-count":70,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179625"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179625","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,6]]}}}