{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T12:54:12Z","timestamp":1782305652689,"version":"3.54.5"},"reference-count":85,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2023,5,21]],"date-time":"2023-05-21T00:00:00Z","timestamp":1684627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P01 HD034430\u201020"],"award-info":[{"award-number":["P01 HD034430\u201020"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Contraction of cardiomyocytes is initiated at subcellular elements called dyads, where L\u2010type Ca<jats:sup>2+<\/jats:sup> channels in t\u2010tubules are located within close proximity to ryanodine receptors in the sarcoplasmic reticulum. While evidence from small rodents indicates that dyads are assembled gradually in the developing heart, it is unclear how this process occurs in large mammals. We presently examined dyadic formation in fetal and newborn sheep (<jats:italic>Ovis aries<\/jats:italic>), and the regulation of this process by fetal cardiac workload. By employing advanced imaging methods, we demonstrated that t\u2010tubule growth and dyadic assembly proceed gradually during fetal sheep development, from 93\u00a0days of gestational age until birth (147\u00a0days). This process parallels progressive increases in fetal systolic blood pressure, and includes step\u2010wise colocalization of L\u2010type Ca<jats:sup>2+<\/jats:sup> channels and the Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchanger with ryanodine receptors. These proteins are upregulated together with the dyadic anchor junctophilin\u20102 during development, alongside changes in the expression of amphiphysin\u20102 (BIN1) and its partner proteins myotubularin and dynamin\u20102. Increasing fetal systolic load by infusing plasma or occluding the post\u2010ductal aorta accelerated t\u2010tubule growth. Conversely, reducing fetal systolic load with infusion of enalaprilat, an angiotensin converting enzyme inhibitor, blunted t\u2010tubule formation. Interestingly, altered t\u2010tubule densities did not relate to changes in dyadic junctions, or marked changes in the expression of dyadic regulatory proteins, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum. In conclusion, augmenting blood pressure and workload during normal fetal development critically promotes t\u2010tubule growth, while additional signals contribute to dyadic assembly.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15567-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>T\u2010tubule growth and dyadic assembly proceed gradually in cardiomyocytes during fetal sheep development, from 93\u00a0days of gestational age until the post\u2010natal stage.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Increasing fetal systolic load by infusing plasma or occluding the post\u2010ductal aorta accelerated t\u2010tubule growth and hypertrophy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In contrast, reducing fetal systolic load by enalaprilat infusion slowed t\u2010tubule development and decreased cardiomyocyte size.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Load\u2010dependent modulation of t\u2010tubule maturation was linked to altered expression patterns of the t\u2010tubule regulatory proteins junctophilin\u20102 and amphiphysin\u20102 (BIN1) and its protein partners.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Altered t\u2010tubule densities did not influence dyadic formation, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284538","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T09:17:15Z","timestamp":1683019035000},"page":"4461-4486","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Augmenting workload drives T\u2010tubule assembly in developing cardiomyocytes"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3802-6690","authenticated-orcid":false,"given":"Ornella","family":"Manfra","sequence":"first","affiliation":[{"name":"Institute for Experimental Medical Research Oslo University Hospital and University of Oslo  Oslo Norway"},{"name":"K.G. 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