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

Area of Science:

• Cardiology
• Endocrinology
• Molecular Biology

Background:

• Glucocorticoid levels increase in late gestation for fetal organ maturation.
• Immature fetal heart function poses survival risks.
• Cardiomyocyte glucocorticoid receptor (GR) is crucial for fetal heart development in vivo, but mechanisms are unclear.

Purpose of the Study:

• To investigate if GR activation in isolated fetal cardiomyocytes in vitro induces similar maturational changes as observed in vivo.
• To identify molecular mechanisms underlying glucocorticoid-induced fetal heart maturation.

Main Methods:

• Primary mouse fetal cardiomyocytes were treated with physiologically relevant glucocorticoid levels.
• Contractility, Z-disc assembly, myofibril development, and mitochondrial activity were assessed.
• RNA sequencing and siRNA-mediated PGC-1α knockdown were used to identify molecular targets and mediators.

Main Results:

• Glucocorticoid treatment improved cardiomyocyte contractility, Z-disc assembly, and myofibril formation.
• Mitochondrial activity and expression of PGC-1α, a key regulator of mitochondrial capacity, were increased.
• Knockdown of PGC-1α abolished glucocorticoid-induced effects on myofibril structure and mitochondrial function.
• RNA sequencing identified PGC-1α and other transcriptional regulators as primary GR targets.

Conclusions:

• GR activation in fetal cardiomyocytes in vitro recapitulates key maturational changes observed in vivo.
• PGC-1α is a critical mediator of glucocorticoid-induced fetal cardiomyocyte maturation, particularly affecting structure and mitochondrial function.
• Other identified transcriptional regulators may also play significant roles in the fetal-to-neonatal heart transition.