Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes

Jessica R. Ivy, Roderic N. Carter, Jin-Feng Zhao, Charlotte Buckley, Helena Urquijo, Eva A. Rog-Zielinska, Emma Panting, Lenka Hrabalkova, Cara Nicholson, Emma J. Agnew, Matthew W. Kemp, Nicholas M. Morton, Sarah J. Stock, Caitlin Wyrwoll, Ian G. Ganley, Karen E. Chapman (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Number of pages24
JournalThe Journal of Physiology
Early online date10 Sep 2021
DOIs
Publication statusE-pub ahead of print - 10 Sep 2021

Keywords

  • antenatal corticosteroids
  • cardiomyocytes
  • early-life programming
  • glucocorticoid
  • heart
  • preterm birth

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