{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T14:29:37Z","timestamp":1773930577781,"version":"3.50.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2018,3,27]],"date-time":"2018-03-27T00:00:00Z","timestamp":1522108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RG\/11\/20\/29266"],"award-info":[{"award-number":["RG\/11\/20\/29266"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/12\/24\/29568"],"award-info":[{"award-number":["FS\/12\/24\/29568"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RE\/13\/4\/30184"],"award-info":[{"award-number":["RE\/13\/4\/30184"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["AZV 16-27317A"],"award-info":[{"award-number":["AZV 16-27317A"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    The inherited cardiomyopathies, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are relatively common, potentially life-threatening and currently untreatable. Mutations are often in the contractile proteins of cardiac muscle and cause abnormal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    regulation\n                    <jats:italic>via<\/jats:italic>\n                    troponin. HCM is usually linked to higher myofilament Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -sensitivity whilst in both HCM and DCM mutant tissue there is often an uncoupling of the relationship between troponin I (TnI) phosphorylation by PKA and modulation of myofilament Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -sensitivity, essential for normal responses to adrenaline. The adrenergic response is blunted, and this may predispose the heart to failure under stress. At present there are no compounds or interventions that can prevent or treat sarcomere cardiomyopathies. There is a need for novel therapies that act at a more fundamental level to affect the disease process. We demonstrated that epigallocatechin-3 gallate (EGCG) was found to be capable of restoring the coupled relationship between Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -sensitivity and TnI phosphorylation in mutant thin filaments to normal\n                    <jats:italic>in vitro<\/jats:italic>\n                    , independent of the mutation (15 mutations tested). We have labeled this property \u201cre-coupling.\u201d The action of EGCG\n                    <jats:italic>in vitro<\/jats:italic>\n                    to reverse the abnormality caused by myopathic mutations would appear to be an ideal pharmaceutical profile for treatment of inherited HCM and DCM but EGCG is known to be promiscuous\n                    <jats:italic>in vivo<\/jats:italic>\n                    and is thus unsuitable as a therapeutic drug. We therefore investigated whether other structurally related compounds can re-couple myofilaments without these off-target effects. We used the quantitative\n                    <jats:italic>in vitro<\/jats:italic>\n                    motility assay to screen 40 compounds, related to C-terminal Hsp90 inhibitors, and found 23 that can re-couple mutant myofilaments. There is no correlation between re-couplers and Hsp90 inhibitors. The Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -sensitivity shift due to TnI phosphorylation was restored to 2.2 \u00b1 0.01-fold (\n                    <jats:italic>n<\/jats:italic>\n                    = 19) compared to 2.0 \u00b1 0.24-fold (\n                    <jats:italic>n<\/jats:italic>\n                    = 7) in wild-type thin filaments. Many of these compounds were either pure re-couplers or pure desensitizers, indicating these properties are independent; moreover, re-coupling ability could be lost with small changes of compound structure, indicating the possibility of specificity. Small molecules that can re-couple may have therapeutic potential.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>HIGHLIGHTS<\/jats:bold>\n                    <jats:list>\n                      <jats:list-item>\n                        <jats:p>- Inherited cardiomyopathies are common diseases that are currently untreatable at a fundamental level and therefore finding a small molecule treatment is highly desirable.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          - We have identified a molecular level dysfunction common to nearly all mutations: uncoupling of the relationship between troponin I phosphorylation and modulation of myofilament Ca\n                          <jats:sup>2+<\/jats:sup>\n                          -sensitivity, essential for normal responses to adrenaline.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          - We have identified a new class of drugs that are capable of both reducing Ca\n                          <jats:sup>2+<\/jats:sup>\n                          -sensitivity and\/or recouping the relationship between troponin I phosphorylation and Ca\n                          <jats:sup>2+<\/jats:sup>\n                          -sensitivity.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>- The re-coupling phenomenon can be explained on the basis of a single mechanism that is testable.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>- Measurements with a wide range of small molecules of varying structures can indicate the critical molecular features required for recoupling and allows the prediction of other potential re-couplers.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.3389\/fphys.2018.00243","type":"journal-article","created":{"date-parts":[[2018,3,27]],"date-time":"2018-03-27T10:45:34Z","timestamp":1522147534000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Molecular Defects in Cardiac Myofilament Ca2+-Regulation Due to Cardiomyopathy-Linked Mutations Can Be Reversed by Small Molecules Binding to Troponin"],"prefix":"10.3389","volume":"9","author":[{"given":"Alice","family":"Sheehan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew E.","family":"Messer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Papadaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afnan","family":"Chaudhry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladim\u00edr","family":"Kren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Biedermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Blagg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuj","family":"Khandelwal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven B.","family":"Marston","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2018,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/S0006-291X(02)00852-5","article-title":"Expression and biological activity of Baculovirus generated wild-type human slow alpha tropomyosin and the Met9Arg mutant responsible for a dominant form of nemaline myopathy","volume":"296","author":"Akkari","year":"2002","journal-title":"Biochem. 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