Metabolic Determinants of Cardiomyocyte Proliferation

Abstract

The adult mammalian heart is recalcitrant to regeneration after injury, in part due to the postmitotic nature of cardiomyocytes. Accumulating evidence suggests that cardiomyocyte proliferation in fetal or neonatal mammals and in regenerative non-mammalian models depends on a conducive metabolic state. Results from numerous studies in adult hearts indicate that conditions of relatively low fatty acid oxidation, low reactive oxygen species generation, and high glycolysis are required for induction of cardiomyocyte proliferation. Glycolysis appears particularly important because it provides branchpoint metabolites for several biosynthetic pathways that are essential for synthesis of nucleotides and nucleotide sugars, amino acids, and glycerophospholipids, all of which are required for daughter cell formation. In addition, the proliferative cardiomyocyte phenotype is supported in part by relatively low oxygen tensions and through the actions of critical transcription factors, coactivators, and signaling pathways that promote a more glycolytic and proliferative cardiomyocyte phenotype, such as hypoxia inducible factor 1α (Hif1α), Yes-associated protein (Yap), and ErbB2. Interventions that inhibit glycolysis or its integrated biosynthetic pathways almost universally impair cardiomyocyte proliferative capacity. Furthermore, metabolic enzymes that augment biosynthetic capacity such as phosphoenolpyruvate carboxykinase 2 and pyruvate kinase M2 appear to be amplifiers of cardiomyocyte proliferation. Collectively, these studies suggest that acquisition of a glycolytic and biosynthetic metabolic phenotype is a sine qua non of cardiomyocyte proliferation. Further knowledge of the regulatory mechanisms that control substrate partitioning to coordinate biosynthesis with energy provision could be leveraged to prompt or augment cardiomyocyte division and to promote cardiac repair.

Graphical abstract

Figure 1.

Fundamental metabolic differences in mitotic and non-mitotic cells. To support the demands of proliferation, dividing cells take up more glucose and amino acids such as glutamine, which provide the carbon and nitrogen sources for catabolic processes and biosynthetic reactions. The pentose phosphate pathway (light green) regenerates NADPH, which provides reducing power to biosynthesis and to combat oxidative stress, and branches into nucleotide biosynthetic and NAD(P)+ synthesis pathways. The hexosamine biosynthetic pathway (light blue) produces UDP-Glc(Gal)NAc, which is important for glycosylation reactions that regulate protein folding and for O-GlcNAcylation. Although the glycerol backbone of phospholipids is synthesized via the glycolytic precursor dihydroxacetone phosphate (DHAP) via the glycerolipid synthesis pathway (brown), the fatty acyl chains can be synthesized via carbon engendered in the Krebs cycle. The serine biosynthesis pathway (yellow) is also important for serine and glycine synthesis and the formation of methyl donors such as methylene tetrahydrofolate and for NADPH regeneration. Figure adapted from ref.

Figure 2.

Metabolic phenotypes of fetal and adult cardiomyocytes. Fetal mammalian cardiomyocytes appear more reliant on glycolysis for energy compared with adult myocytes, which supply the majority of their ATP demand by oxidizing fatty acids. In addition, the fetal heart has been suggested to accumulate glycogen to higher levels and have higher pentose phosphate pathway (PPP) activity. Because end products of biosynthetic pathways are required for daughter cell formation, it is also expected that fetal hearts synthesize relatively more nucleotides and have higher hexosamine biosynthetic pathway (HBP), glycerolipid synthesis pathway (GLP), and serine biosynthesis pathway activity (SBP) than the adult heart.

Figure 3.

Working model displaying current knowledge of the influences of metabolism in cardiomyocyte proliferation. Conditions of high oxygen tension, high reactive oxygen species (ROS) levels, and high rates of fatty acid and succinate oxidation impede cardiomyocyte proliferation. Conversely, hypoxia and associated upregulation of Hif1α support high rates of glycolysis, which appears to be required for myocyte division. Enzymes that can support biosynthetic pathways such as pyruvate kinase M2 (Pkm2) and phosphoenolpyruvate carboxykinase 2 (Pck2) have been shown to augment cardiomyocyte proliferative capacity. Other processes related to biosynthesis, such as the mevalonate pathway, protein O-GlcNAcylation, and NAD⁺ biosynthesis also appear to support a proliferative cardiomyocyte phenotype.