title: Glucocorticoids promote structural and functional maturation of foetal cardiomyocytes: a role for PGC-1α.
abstract: Glucocorticoid levels rise dramatically in late gestation to mature foetal organs in readiness for postnatal life. Immature heart function may compromise survival. Cardiomyocyte glucocorticoid receptor (GR) is required for the structural and functional maturation of the foetal heart in vivo, yet the molecular mechanisms are largely unknown. Here we asked if GR activation in foetal cardiomyocytes in vitro elicits similar maturational changes. We show that physiologically relevant glucocorticoid levels improve contractility of primary-mouse-foetal cardiomyocytes, promote Z-disc assembly and the appearance of mature myofibrils, and increase mitochondrial activity. Genes induced in vitro mimic those induced in vivo and include PGC-1α, a critical regulator of cardiac mitochondrial capacity. SiRNA-mediated abrogation of the glucocorticoid induction of PGC-1α in vitro abolished the effect of glucocorticoid on myofibril structure and mitochondrial oxygen consumption. Using RNA sequencing we identified a number of transcriptional regulators, including PGC-1α, induced as primary targets of GR in foetal cardiomyocytes. These data demonstrate that PGC-1α is a key mediator of glucocorticoid-induced maturation of foetal cardiomyocyte structure and identify other candidate transcriptional regulators that may play critical roles in the transition of the foetal to neonatal heart.
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Rog-Zielinska
authors.affiliation: Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, UK.
authors.forename: M-A
authors.initials: MA
authors.lastname: Craig
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Manning
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: R V
authors.initials: RV
authors.lastname: Richardson
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Gowans
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Dunbar
authors.affiliation: Edinburgh Genomics, Ashworth Building, King's Buildings, University of Edinburgh, Edinburgh, UK.
authors.forename: K
authors.initials: K
authors.lastname: Gharbi
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: Holmes
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Hardie
authors.affiliation: Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, UK.
authors.forename: G L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: K E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D000818:Animals; D005318:Fetal Heart / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors