TY - JOUR
T1 - Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes
AU - Ivy, Jessica R.
AU - Carter, Roderic N.
AU - Zhao, Jin-Feng
AU - Buckley, Charlotte
AU - Urquijo, Helena
AU - Rog-Zielinska, Eva A.
AU - Panting, Emma
AU - Hrabalkova, Lenka
AU - Nicholson, Cara
AU - Agnew, Emma J.
AU - Kemp, Matthew W.
AU - Morton, Nicholas M.
AU - Stock, Sarah J.
AU - Wyrwoll, Caitlin
AU - Ganley, Ian G.
AU - Chapman, Karen E.
N1 - Funding Information:
This work was supported by an MRC Project grant (MR/P002811/1), a BHF Centre of Excellence award (RE/13/3/30183), BHF studentships (FS/13/52/30637 to EJA and FS/08/065 to ER‐Z), MRC funding to IGG (MC_UU_00018/2), a Wellcome Trust Clinial Career Development Fellowship (209560/Z/17/Z to SJS), a grant from the Western Australia Channel 7 Telethon Trust (MWK), RNC was funded by a WT New Investigator Award (100981/Z/13/Z) to NMM.
Publisher Copyright:
© 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - antenatal corticosteroids
KW - cardiomyocytes
KW - early-life programming
KW - glucocorticoid
KW - heart
KW - preterm birth
UR - http://www.scopus.com/inward/record.url?scp=85115978078&partnerID=8YFLogxK
U2 - 10.1113/JP281860
DO - 10.1113/JP281860
M3 - Article
C2 - 34505639
SN - 0022-3751
VL - 599
SP - 4901
EP - 4924
JO - The Journal of Physiology
JF - The Journal of Physiology
IS - 21
ER -