{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T10:21:12Z","timestamp":1779099672051,"version":"3.51.4"},"reference-count":46,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the\n                      <jats:italic>TNNT1<\/jats:italic>\n                      and\n                      <jats:italic>TNNT3<\/jats:italic>\n                      genes, respectively. Nonsense or missense\n                      <jats:italic>TNNT1<\/jats:italic>\n                      variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how\n                      <jats:italic>TNNT1<\/jats:italic>\n                      mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with\n                      <jats:italic>TNNT1<\/jats:italic>\n                      \u2010related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post\u2010translational modifications. We also observed that, in the presence of\n                      <jats:italic>TNNT1<\/jats:italic>\n                      variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper\u2010contractility, and then inhibitors of altered contractility as potential therapeutic modalities for\n                      <jats:italic>TNNT1<\/jats:italic>\n                      \u2010associated NM.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16733-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            No therapeutic treatment exists for patients with genetic\n                            <jats:italic>TNNT1<\/jats:italic>\n                            mutations and skeletal muscle weakness\/contractures.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In these patients, expression and post\u2010translational modifications of troponin T are severely disrupted.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These are associated with changes in thin filament compliance where troponin T is located.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>All these induce muscle fibre hyper\u2010contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp288109","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T03:39:03Z","timestamp":1746416343000},"page":"3533-3550","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pathogenic\n                    <i>TNNT1<\/i>\n                    variants are associated with aberrant thin filament compliance and myofibre hyper\u2010contractility"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0076-3038","authenticated-orcid":false,"given":"Jenni","family":"Laitila","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen  Copenhagen Denmark"},{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland and Department of Medical Genetics University of Helsinki  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher T. A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4278-4221","authenticated-orcid":false,"given":"Anthony L.","family":"Hessel","sequence":"additional","affiliation":[{"name":"Institute of Physiology II University of Muenster  Muenster Germany"},{"name":"Accelerated Muscle Biotechnologies  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-7008","authenticated-orcid":false,"given":"Guido","family":"Primiano","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS  Rome Italy"},{"name":"Dipartimento di Neuroscienze Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurelio","family":"Hernandez\u2010Lain","sequence":"additional","affiliation":[{"name":"Neuropathology Unit, Department of Pathology 12 de Octubre University Hospital  Madrid Spain"},{"name":"4imas12 Research Institute, Rare Diseases Network Biomedical Research Center (CIBERER) 12 de Octubre University Hospital  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry, IRCCS Istituto G. Gaslini DINOGMI University of Genova  Genova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael W.","family":"Lawlor","sequence":"additional","affiliation":[{"name":"Diverge Translational Science Laboratory and Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coen A. C.","family":"Ottenheijm","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology  De Boelelaan Amsterdam Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinz","family":"Jungbluth","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine King's College London  London UK"},{"name":"Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital Guy's and St Thomas\u2019 Hospital NHS Foundation Trust  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9779-7678","authenticated-orcid":false,"given":"Ka Fu","family":"Man","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Physical and Chemical Sciences Queen Mary University of London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"Fornili","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Physical and Chemical Sciences Queen Mary University of London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6358-2920","authenticated-orcid":false,"given":"Julien","family":"Ochala","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24885"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2022.11.2942"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0582-9"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2016.04.013"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00047.2023"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.09.005"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI179111"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg2841"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12810"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btg362"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy233"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.2.853"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005826"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46957-7"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2209441119"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31824e8ebe"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1086\/303089"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25144"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2016.08.004"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.325"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2010.055269"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP286870"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12307"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24528"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27678"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10262"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10123428"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1001733107"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr084"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp168"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2021.03.001"},{"issue":"1","key":"e_1_2_6_34_1","article-title":"High\u2010resolution cryo\u2010EM structure of the junction region of the native cardiac thin filament in relaxed state","volume":"2","author":"Risi C. 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