Please use this identifier to cite or link to this item: https://doi.org/10.1113/jp281860
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dc.titleGlucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes
dc.contributor.authorIvy, Jessica R.
dc.contributor.authorCarter, Roderic N.
dc.contributor.authorZhao, Jin-Feng
dc.contributor.authorBuckley, Charlotte
dc.contributor.authorUrquijo, Helena
dc.contributor.authorRog-Zielinska, Eva A.
dc.contributor.authorPanting, Emma
dc.contributor.authorHrabalkova, Lenka
dc.contributor.authorNicholson, Cara
dc.contributor.authorAgnew, Emma J.
dc.contributor.authorKemp, Matthew W.
dc.contributor.authorMorton, Nicholson N.
dc.contributor.authorStock, Sarah J.
dc.contributor.authorWyrwoll, Caitlin
dc.contributor.authorGanley, Ian G.
dc.contributor.authorChapman, Karen E.
dc.date.accessioned2022-10-11T08:07:23Z
dc.date.available2022-10-11T08:07:23Z
dc.date.issued2021-09-30
dc.identifier.citationIvy, Jessica R., Carter, Roderic N., Zhao, Jin-Feng, Buckley, Charlotte, Urquijo, Helena, Rog-Zielinska, Eva A., Panting, Emma, Hrabalkova, Lenka, Nicholson, Cara, Agnew, Emma J., Kemp, Matthew W., Morton, Nicholson N., Stock, Sarah J., Wyrwoll, Caitlin, Ganley, Ian G., Chapman, Karen E. (2021-09-30). Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes. Journal of Physiology 599 (21) : 4901-4924. ScholarBank@NUS Repository. https://doi.org/10.1113/jp281860
dc.identifier.issn0022-3751
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/232201
dc.description.abstractAbstract: The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesized that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon a glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In vivo, in neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes. However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24 h later. Instead, at E17.5, fatty acid oxidation genes were downregulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was also downregulated in fetal hearts at E17.5, 24 h after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a translational sheep model of preterm birth, both GR and PGC-1α were downregulated in heart. These data suggest that endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by downregulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility. Key points: Glucocorticoids are steroid hormones that play a vital role in late pregnancy in maturing fetal organs, including the heart. In fetal cardiomyocytes in culture, glucocorticoids promote mitochondrial fatty acid oxidation, suggesting they facilitate the perinatal switch from carbohydrates to fatty acids as the predominant energy substrate. Administration of a synthetic glucocorticoid in late pregnancy in mice downregulates the glucocorticoid receptor and interferes with the normal increase in genes involved in fatty acid metabolism in the heart. In a sheep model of preterm birth, antenatal corticosteroids (synthetic glucocorticoid) downregulates the glucocorticoid receptor and the gene encoding PGC-1α, a master regulator of energy metabolism. These experiments suggest that administration of antenatal corticosteroids in anticipation of preterm delivery may interfere with fetal heart maturation by downregulating the ability to respond to glucocorticoids. © 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
dc.publisherJohn Wiley and Sons Inc
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2021
dc.subjectantenatal corticosteroids
dc.subjectcardiomyocytes
dc.subjectearly-life programming
dc.subjectglucocorticoid
dc.subjectheart
dc.subjectpreterm birth
dc.typeArticle
dc.contributor.departmentDEPT OF OBSTETRICS & GYNAECOLOGY
dc.description.doi10.1113/jp281860
dc.description.sourcetitleJournal of Physiology
dc.description.volume599
dc.description.issue21
dc.description.page4901-4924
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