Glucocorticoids promote structural and functional maturation of foetal cardiomyocytes: a role for PGC-1α

E. A. Rog-Zielinska, M. A. Craig, J. R. Manning, R. V. Richardson, G. J. Gowans, D. R. Dunbar, K. Gharbi, C. J. Kenyon, M. C. Holmes, D. G. Hardie, G. L. Smith, K. E. Chapman (Lead / Corresponding author)

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    41 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)1106-1116
    Number of pages11
    JournalCell Death & Differentiation
    Volume22
    Issue number7
    Early online date31 Oct 2014
    DOIs
    Publication statusPublished - 1 Jul 2015

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