ABSTRACT
The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesised 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 glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes in vivo. 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 hours later. Instead, at E17.5, fatty acid oxidation genes were down-regulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was down-regulated in vivo in fetal hearts at E17.5, 24 hours after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a sheep model of preterm birth, both GR and PGC-1α were down-regulated in fetal heart. These data suggest 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 down-regulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
FUNDING: 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
ABBREVIATIONS
- GR
- glucocorticoid receptor
- E
- embryonic day
- P
- postnatal day
- PBS
- phosphate buffered saline
- SRB
- sulforhodamine B
- 2DG
- 2 deoxyglucose
- AR
- antimycin and rotenone
- OCR
- oxygen consumption rate
- ECAR
- extracellular acidification rate
- FCCP
- carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone
- BSA
- bovine serum albumin
- GFP
- green fluorescent protein
- DFP
- deferiprone
- CPT-1
- carnitine palmitoyltransferase-1
- PGC-1α – PPARγ
- coactivator-1α
- SD
- standard deviation