A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth

Figure 1. Cardiomyocyte transition from proliferation to quiescence occurs at different times in zebrafish, rodents and large mammals During embryonic development, when oxygen is low (deep blue section of arrow), CMs undergo proliferation (green bars) and remain mononucleated. Postnatal CMs in zebrafish remain proliferative throughout life despite low oxygen, whilst rodent CMs exit the cell cycle and become non‐proliferative (red bars) within 3−7 days after birth when oxygen increases (lighter blue arrow). In contrast, this transition event occurs during late gestation in large mammals when oxygen levels are low. Heart volume can only increase by hypertrophic growth of pre‐existing CMs and mononucleated CMs become binucleated or in the case of pigs even multinucleated. Adapted from Lock et al. (2018).

Figure 2. Cortisol and thyroid hormone concentrations and resulting cardiomyocyte number and binucleation after birth in rats and in late‐gestation sheep fetuses In rats, there is a steep surge in circulating corticosterone and thyroid hormone (T3) postnatally at P10, leading to a proliferative burst of CMs at P15. In sheep, the surge in cortisol and circulating T3 occurs during late gestation (∼135–145d GA), which coincides with the cessation of proliferation and rise in binucleation in CMs.

Figure 3. Regulation of the fetal cardiac cell cycle by miRNAs There is a complex interplay of miRNA regulation and the cell cycle. The miRNA‐15 family, the Let‐7 family, miRNA‐240 and miRNA‐302 are miRNAs that inhibit CDK/cyclin complexes at various points in the cell cycle. The miRNA‐17/92 cluster, miRNA‐302/376 cluster, miRNA‐199‐3p and miRNA‐590‐3p negatively regulate cell cycle inhibitors allowing for proliferation. Note many more miRNAs interact with the cell cycle and this figure represents a simplified version.

Figure 4. Regulation of cardiac metabolism by miRNAs before and after birth miRNAs regulate many aspects of glucose and lipid metabolism in the heart. miRNA‐133, ‐150, ‐155 and ‐223 and the Let‐7 family regulate glucose transport via modulating the expression of GLUT4. miRNA‐27a‐3p, ‐125b, ‐135 and ‐199a promote glycolysis whilst miRNA‐138 has been shown to inhibit the glycolysis pathway. miRNA‐195 increases acylation of pyruvate dehydrogenase (PDH) to promote conversion of pyruvate to acetyl‐CoA. The Let‐7 family promotes FAO whilst miRNA‐33a/b, ‐132 and ‐212 repress various enzymes involved in the pathway. miRNA‐140, ‐499 and ‐761 regulate the TCA cycle inside the mitochondria, and miRNA‐181c and miRNA‐210 are involved in ETC remodelling via suppression of complex 2 (SDHB) and 4 (MTCO1). Note many more miRNAs interact with the metabolic pathways and this figure represents a simplified version.

Figure 5. Overview of the formation and release of exosomes from cells and their use as biomarkers of disease Numerous diseases including heart disease, brain/neurodegenerative disease, renal disease, cancer and even physiological alterations such as pregnancy can be detected via miRNAs packaged into circulating exosomes released into the bloodstream or other bodily fluids such as saliva and urine. Circulating exosomal miRNAs are an attractive diagnostic target due to their non‐invasive nature.