{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T08:36:15Z","timestamp":1793349375170,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2018-30 (CVON-PREDICT2)"],"award-info":[{"award-number":["2018-30 (CVON-PREDICT2)"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023794","name":"PLN Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["202008230186"],"award-info":[{"award-number":["202008230186"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMW","doi-asserted-by":"publisher","award":["91111.006"],"award-info":[{"award-number":["91111.006"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Phospholamban (PLN) acts as an inhibitory regulator of calcium uptake in the sarco-\/endoplasmic reticulum (SR) of cardiomyocytes. The pathogenic variant, PLN-R14del, leads to dilated and\/or arrhythmogenic cardiomyopathy. Previous studies demonstrated that PLN-targeting antisense oligonucleotides (ASOs) can mitigate disease progression in mice. However, it remains unclear whether the protective effects of PLN-ASO therapy are due to improved calcium homeostasis or via reduction of abnormal PLN-SR clusters, a hallmark of this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Homozygous PLN-R14del (R14\u0394\/\u0394) mice were randomized to injections with various doses of PLN-ASO (3, 7, 15, or 25\u2005mg\/kg) or a scrambled control. Consistent with previous findings, R14\u0394\/\u0394 mice exhibited severe cardiac dysfunction, myocardial fibrosis, and aberrant SR clusters by 7 weeks of age. ASO-treated R14\u0394\/\u0394 mice displayed a dose-dependent preservation of cardiac function with diminished remodelling and extended lifespan. Correspondingly, abnormal PLN-SR clustering was diminished by ASO therapy in a dose-dependent manner, and SR structure returned to a normal state. Calcium dynamics were investigated separately on isolated cardiomyocytes from treated mice. In wild-type (WT) mice, ASO (25\u2005mg\/kg) mediated PLN depletion significantly enhanced calcium and contractile dynamics, confirming effective target engagement. In R14\u0394\/\u0394 cardiomyocytes, however, ASO treatment showed limited effects on calcium dynamics. Calcium transient decay and sarcomeric shortening were already enhanced in R14\u0394\/\u0394 cardiomyocytes compared to WT, suggesting a partial loss of the PLN-R14del calcium inhibitory function. This pre-existing acceleration of calcium dynamics likely accounts for the limited impact of ASO therapy on calcium regulation in R14\u0394\/\u0394 mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PLN-ASO treatment demonstrated a dose-dependent restoration of SR organization and a concomitant increase in lifespan in PLN-R14del mice. The enhanced SR calcium uptake in PLN-R14del mice suggests a partial loss of inhibitory function, limiting ASO therapy's effects on calcium dynamics. This implies that PLN-ASO therapy acts predominantly via restoration of SR structure in PLN-R14del cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf156","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T08:57:27Z","timestamp":1756976247000},"page":"2042-2054","source":"Crossref","is-referenced-by-count":4,"title":["In PLN-R14del mice, SR structure restoration, rather than calcium cycling, is the dominant effector of PLN-ASO treatment"],"prefix":"10.1093","volume":"121","author":[{"given":"Liu","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen , Hanzeplein 1, Groningen 9713 GZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim R","family":"Eijgenraam","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen , Hanzeplein 1, Groningen 9713 GZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Amilon","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca , Gothenburg ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Janz\u00e9n","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca , Gothenburg ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny M","family":"Hansson","sequence":"additional","affiliation":[{"name":"Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca , Gothenburg ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter A","family":"Kubli","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals , Carlsbad, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Sp\u00e4ter","sequence":"additional","affiliation":[{"name":"Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca , Gothenburg ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam E","family":"Mullick","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals , Carlsbad, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-4413","authenticated-orcid":false,"given":"Peter","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University 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