{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:25:01Z","timestamp":1792787101722,"version":"4.5.0"},"reference-count":59,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T00:00:00Z","timestamp":1551225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union's Horizon 2020","award":["647714"],"award-info":[{"award-number":["647714"]}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<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>As reactivation of the fetal gene program has been implicated in pathological remodelling during heart failure (HF), we examined whether cardiomyocyte subcellular structure and function revert to an immature phenotype during this disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Surface and internal membrane structures appeared gradually during development, and returned to a juvenile state during HF. Similarly, dyadic junctions between the cell membrane and sarcoplasmic reticulum were progressively \u2018packed\u2019 with L\u2010type Ca\n                            <jats:sup>2+<\/jats:sup>\n                            channels and ryanodine receptors during development, and \u2018unpacked\u2019 during HF.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Despite similarities in subcellular structure, dyads were observed to be functional from early developmental stages, but exhibited an impaired ability to release Ca\n                            <jats:sup>2+<\/jats:sup>\n                            in failing cardiomyocytes.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Thus, while immature and failing cardiomyocytes share similarities in subcellular structure, these do not fully account for the marked impairment of Ca\n                            <jats:sup>2+<\/jats:sup>\n                            homeostasis observed in HF.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Reactivation of the fetal gene programme has been implicated as a driver of pathological cardiac remodelling. Here we examined whether pathological remodelling of cardiomyocyte substructure and function during heart failure (HF) reflects a reversion to an immature phenotype. Using scanning electron microscopy, we observed that Z\u2010grooves and t\u2010tubule openings at the cell surface appeared gradually during cardiac development, and disappeared during HF. Confocal and super\u2010resolution imaging within the cell interior revealed similar structural parallels; disorganization of t\u2010tubules in failing cells was strikingly reminiscent of the late stages of postnatal development, with fewer transverse elements and a high proportion of longitudinal tubules. Ryanodine receptors (RyRs) were observed to be laid down in advance of developing t\u2010tubules and similarly \u2018orphaned\u2019 in HF, although RyR distribution along Z\u2010lines was relatively sparse. Indeed, nanoscale imaging revealed coordinated packing of L\u2010type Ca\n                      <jats:sup>2+<\/jats:sup>\n                      channels and RyRs into dyadic junctions during development, and orderly unpacking during HF. These findings support a \u2018last in, first out\u2019 paradigm, as the latest stages of dyadic structural development are reversed during disease. Paired imaging of t\u2010tubules and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      showed that the disorganized arrangement of dyads in immature and failing cells promoted desynchronized and slowed Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release in these two states. However, while developing cells exhibited efficient triggering of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release at newly formed dyads, dyadic function was impaired in failing cells despite similar organization of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling proteins. Thus, pathologically deficient Ca\n                      <jats:sup>2+<\/jats:sup>\n                      homeostasis during HF is only partly linked to the re\u2010emergence of immature subcellular structure, and additionally reflects lost dyadic functionality.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp277273","type":"journal-article","created":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T12:44:04Z","timestamp":1549025044000},"page":"1833-1853","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Cardiomyocyte substructure reverts to an immature phenotype during heart failure"],"prefix":"10.1113","volume":"597","author":[{"given":"D. B.","family":"Lipsett","sequence":"first","affiliation":[{"name":"Institute for Experimental Medical Research Oslo University Hospital and University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Frisk","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research Oslo University Hospital and University of Oslo  Oslo Norway"},{"name":"KG Jebsen Center for Cardiac Research University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. M.","family":"Aronsen","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research Oslo University Hospital and University of Oslo  Oslo Norway"},{"name":"Bj\u00f8rknes College  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. S.","family":"Nord\u00e9n","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research Oslo University Hospital and University of Oslo  Oslo Norway"},{"name":"KG Jebsen Center for Cardiac Research University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6530-6797","authenticated-orcid":false,"given":"O. 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