Energy Metabolic Phenotype of the Cardiomyocyte During Development, Differentiation, and Postnatal Maturation

Abstract

Dramatic maturational changes occur in cardiac energy metabolism during cardiac development, differentiation, and postnatal growth. These changes in energy metabolism have important impacts on the ability of the cardiomyocyte to proliferate during early cardiac development, as well as when cardiomyocytes terminally differentiate during later development. During early cardiac development, glycolysis is a major source of energy for proliferating cardiomyocytes. As cardiomyocytes mature and become terminally differentiated, mitochondrial oxidative capacity increases, with fatty acid beta-oxidation becoming a major source of energy for the heart. The increase in mitochondrial oxidative capacity seems to coincide with a decrease in the proliferative ability of the cardiomyocyte. The switch from glycolysis to mitochondrial oxidative metabolism during cardiac development includes both alterations in the transcriptional control and acute alterations in the control of each pathway. Interestingly, if a hypertrophic stress is placed on the adult heart, cardiac energy metabolism switches to a more fetal phenotype, which includes an increase in glycolysis and decrease in mitochondrial fatty acid beta-oxidation. In this article, we review the impact of alterations in energy substrate metabolism on cardiomyocyte proliferation, differentiation, and postnatal maturation.

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

“…We next determined the effect of an adult-like lipogenic milieu on neonatal cardiomyocytes by treatment with a 3F protocol consisting of insulin, 3-isobutylmethylxanthine, and dexamethasone for 10 days (23). In control cardiomyocytes, the 3F protocol switched the embryo-like metabolism dominated by glycolysis (25) to an adult-like metabolism, which was characterized by an increased baseline OCR (Fig. 1E), and more fatty acid ␤-oxidation (Fig.…”

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

“…This is contrary to observations in intact hearts subjected to hypoxia, which very quickly become depleted of ATP and PCr. Adult cardiomyocytes depend on β ‐oxidation of fatty acids to generate ATP, whereas the neonate cardiomyocytes have not developed β ‐oxidation capabilities and use glycolysis as the main ATP generation pathway (Lopaschuk and Jaswal 2010). RNCMs are thus capable of maintaining constant ATP levels even when subjected to prolonged hypoxic stress.…”

Cardiomyocyte differentiation: Experience and observations from 2 laboratories

“…(21) Thus determining the rate of oxygen respiration would provide an ideal measure of oxidative phosphorylation in differentiated H9c2 cells. It should be noted that this variable was only investigated in cells differentiated for 6 days and no fatty acids were included as the researchers merely aimed to establish if a change in oxygen consumption was evident following differentiation.…”

“…(20) Lopashuk, et al (2010) identified that a switch from glycolysis to oxidative phosphorylation is a fundamental characteristic of differentiated cardiac cells, since cardiomyotubes prefer fatty acids to glucose as a source of fuel. (21) It could be argued that when differentiated, the H9c2 cells would offer a more closely matched representation of adult cardiomyocytes than when undifferentiated. Menard, et al (1999) stated that the H9c2 cells are easy to manipulate, and when differentiated, provide a suitable cardiac cellular model with a maintained cardiac phenotype for a range of investigations commonly challenging to perform on primary cardiomyocytes.…”