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The cardiac remodeling that occurs as the disease develops can mask the pathogenic impact of the mutation. Here, to discriminate between mutation-induced and disease-related changes in myofilament function, we investigate the pathogenic mechanisms underlying HCM in a patient carrying a homozygous mutation (K280N) in the cardiac troponin T gene (TNNT2), which results in 100% mutant cardiac troponin T. We examine sarcomere mechanics and energetics in K280N-isolated myofibrils and demembranated muscle strips, before and after replacement of the endogenous troponin. We also compare these data to those of control preparations from donor hearts, aortic stenosis patients (LVHao), and HCM patients negative for sarcomeric protein mutations (HCMsmn). The rate constant of tension generation following maximal Ca2+ activation (kACT) and the rate constant of isometric relaxation (slow kREL) are markedly faster in K280N myofibrils than in all control groups. Simultaneous measurements of maximal isometric ATPase activity and Ca2+-activated tension in demembranated muscle strips also demonstrate that the energy cost of tension generation is higher in the K280N than in all controls. Replacement of mutant protein by exchange with wild-type troponin in the K280N preparations reduces kACT, slow kREL, and tension cost close to control values. In donor myofibrils and HCMsmn demembranated strips, replacement of endogenous troponin with troponin containing the K280N mutant increases kACT, slow kREL, and tension cost. The K280N TNNT2 mutation directly alters the apparent cross-bridge kinetics and impairs sarcomere energetics. This result supports the hypothesis that inefficient ATP utilization by myofilaments plays a central role in the pathogenesis of the disease.<\/jats:p>","DOI":"10.1085\/jgp.201812160","type":"journal-article","created":{"date-parts":[[2018,12,22]],"date-time":"2018-12-22T05:15:21Z","timestamp":1545455721000},"page":"18-29","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":30,"title":["The homozygous K280N troponin T mutation alters cross-bridge kinetics and energetics in human HCM"],"prefix":"10.1085","volume":"151","author":[{"given":"Nicoletta","family":"Piroddi","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 di Firenze, Florence, Italy 1"}]},{"given":"E. 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1"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3980-683X","authenticated-orcid":true,"given":"Beatrice","family":"Scellini","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 di Firenze, Florence, Italy 1"}]},{"given":"Paul J.M.","family":"Wijnker","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands 2"}]},{"given":"Vasco","family":"Sequiera","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands 2"}]},{"given":"Dennis","family":"Dooijes","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands 2"},{"name":"Clinical Genetics, University Medical Center, Utrecht, Netherlands 4"}]},{"given":"Cristobal","family":"dos Remedios","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, Bosch Institute, The University of Sydney, Sydney, Australia 5"}]},{"given":"Saskia","family":"Schlossarek","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 6"},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Hamburg\/Kiel\/L\u00fcbeck, Germany 7"}]},{"given":"Man Ching","family":"Leung","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College, London, England, UK 8"}]},{"given":"Andrew","family":"Messer","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College, London, England, UK 8"}]},{"given":"Douglas G.","family":"Ward","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK 9"}]},{"given":"Annibale","family":"Biggeri","sequence":"additional","affiliation":[{"name":"DISIA, Universit\u00e0 di Firenze & ISPO Firenze, Florence, Italy 10"}]},{"given":"Chiara","family":"Tesi","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 di Firenze, Florence, Italy 1"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-5820","authenticated-orcid":true,"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 6"},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Hamburg\/Kiel\/L\u00fcbeck, Germany 7"}]},{"given":"Charles S.","family":"Redwood","sequence":"additional","affiliation":[{"name":"Radcliffe Department of Medicine, University of Oxford, Oxford, UK 11"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6054-6070","authenticated-orcid":true,"given":"Steven B.","family":"Marston","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College, London, England, UK 8"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-5788","authenticated-orcid":true,"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands 2"},{"name":"Clinical Genetics, University Medical Center, Utrecht, Netherlands 4"},{"name":"ICIN-Netherlands, Heart Institute, Utrecht, Netherlands. 12"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2624-4778","authenticated-orcid":true,"given":"Corrado","family":"Poggesi","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 di Firenze, Florence, Italy 1"},{"name":"LENS, Sesto Fiorentino (Firenze), 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