Cardiac growth patterns and metabolism before and after birth in swine: Role of miR in proliferation, hypertrophy and metabolism

Abstract

The adult mammalian heart is unable to undergo cardiac repair, limiting potential treatment options after cardiac damage. However, the fetal heart is capable of cardiac repair. In preparation for birth, cardiomyocytes (CMs) undergo major maturational changes that include exit from the cell cycle, hypertrophic growth, and mitochondrial maturation. The timing and regulation of such events in large mammals is not fully understood. In the present study, we aimed to assess this critical CM transition period using pigs as a preclinically relevant model. Left ventricular myocardium from Large White cross Landrace gilts was collected at 91, 98, 106 and 111–113 days gestation (d GA; term = 115d GA) and in piglets at 0–1, 4–5, 14–18, 19–20 days after birth. We found that miR-133a, which has known roles in CM proliferation, was significantly downregulated before birth, before rising postnatally. Likewise, gene expression of PCNA and CDK1 was repressed until birth with a rise postnatally, suggesting a decline in proliferation during late gestation followed by the onset of multinucleation in postnatal life. The timing of the switch in myocardial metabolism was unclear; however, complexes within the electron transport chain and mitochondrial biogenesis followed a similar pattern of decreasing abundance during late gestation and then a rise postnatally. These data suggest that CM maturation events such as cell cycle arrest and mitochondrial maturation occur around birth. These results may prove important to consider for preclinical applications such as the development of new therapeutics for cardiac repair.

Keywords

• Cardiomyocytes
• Proliferation
• Metabolism
• miRNAs
• Cardiac
• Development