Transition from fetal to postnatal state in the heart: Crosstalk between metabolism and regeneration

Abstract

Cardiovascular disease is the leading cause of mortality worldwide. Myocardial injury resulting from ischemia can be fatal because of the limited regenerative capacity of adult myocardium. Mammalian cardiomyocytes rapidly lose their proliferative capacities, with only a small fraction of adult myocardium remaining proliferative, which is insufficient to support post-injury recovery. Recent investigations have revealed that this decline in myocardial proliferative capacity is closely linked to perinatal metabolic shifts. Predominantly glycolytic fetal myocardial metabolism transitions towards mitochondrial fatty acid oxidation postnatally, which not only enables efficient production of ATP but also causes a dramatic reduction in cardiomyocyte proliferative capacity. Extensive research has elucidated the mechanisms behind this metabolic shift, as well as methods to modulate these metabolic pathways. Some of these methods have been successfully applied to enhance metabolic reprogramming and myocardial regeneration. This review discusses recently acquired insights into the interplay between metabolism and myocardial proliferation, emphasizing postnatal metabolic transitions.

Keywords: BCAA; amino acids; cardiac metabolism; environment shift; fatty acid oxidation; glycolysis; heart regeneration; ketone body; mTOR; mitochondria.

FIGURE 1

Glucose metabolism in cardiac regeneration. Glucose is taken up into cells through glucose transporters (Gluts), which are more strongly expressed in the myocardium during the fetal period than postnatally. Glucose is used in the glycolytic system, which branches into the nucleic acid synthesis pathway, known as the pentose phosphate pathway (PPP) and the Polyol pathway. Pkm2, which acts downstream in the glycolytic pathway, links the PPP to angiogenesis and enhances proliferative potential. Interventions such as the overexpression of Glut1, inhibition of Pkm2, or its downstream enzymes Pdk and others, modulate glucose and mitochondrial metabolism and induce cardiac growth and regeneration. Images are created using BioRender.com.

FIGURE 2

Mitochondrial metabolism in myocardial proliferation. Fatty acids are used in the TCA cycle of the mitochondria via Cpt1. Reduction in fatty acid usage by the modulation of Pkm2 (see Figure 1), or by inhibition of Cpt1, reduces fatty acid oxidation and promotes regeneration. Within the TCA cycle, succinate is involved in cell cycle arrest through the generation of reactive oxygen species (ROS), and inhibition of succinate dehydrogenase (SDH) by malonic acid treatment induces proliferation. Images are created using BioRender.com.

FIGURE 3

Triggers for postnatal metabolic shift. During fetal development, glucose metabolism is dominant in the myocardium under hypoxic conditions, maintaining proliferative capacity. This hypoxic metabolism is regulated by genes such as Hif1a and UCP2. Postnatally, changes induced by extracardiac factors such as GLA in breast milk, thyroid hormones, and sympathetic innervation induce reactive oxygen species (ROS) generation through mitochondrial fatty acid oxidation (see Figure 2) and epigenetic alterations via a histone modification enzyme Kdm2. Postnatal metabolic transitions contribute to the loss of cardiac regeneration capacity through these mechanisms, and possibly other unknown pathways. Images are created using BioRender.com.