Metabolic Regulation of Cardiac Regeneration

Abstract

The mortality due to heart diseases remains highest in the world every year, with ischemic cardiomyopathy being the prime cause. The irreversible loss of cardiomyocytes following myocardial injury leads to compromised contractility of the remaining myocardium, adverse cardiac remodeling, and ultimately heart failure. The hearts of adult mammals can hardly regenerate after cardiac injury since adult cardiomyocytes exit the cell cycle. Nonetheless, the hearts of early neonatal mammals possess a stronger capacity for regeneration. To improve the prognosis of patients with heart failure and to find the effective therapeutic strategies for it, it is essential to promote endogenous regeneration of adult mammalian cardiomyocytes. Mitochondrial metabolism maintains normal physiological functions of the heart and compensates for heart failure. In recent decades, the focus is on the changes in myocardial energy metabolism, including glucose, fatty acid, and amino acid metabolism, in cardiac physiological and pathological states. In addition to being a source of energy, metabolites are becoming key regulators of gene expression and epigenetic patterns, which may affect heart regeneration. However, the myocardial energy metabolism during heart regeneration is majorly unknown. This review focuses on the role of energy metabolism in cardiac regeneration, intending to shed light on the strategies for manipulating heart regeneration and promoting heart repair after cardiac injury.

Keywords: amino acid metabolism; cardiomyocyte proliferation; fatty acid metabolism; glucose metabolism; heart regeneration; metabolism regulation.

FIGURE 1

Comparison of the regenerative capacity of representative lower vertebrates, neonatal, and adult mammals. Hypoxia can promote heart regeneration and increase the regenerative capacity. During the growth of neonatal mice, the shift in metabolic state of the heart due to the increased oxygen and nutrients leads to a decrease in the myocardial regenerative capacity.

FIGURE 2

Different metabolic patterns in physiological and pathological states affect the myocardial regenerative capacity. (A) Under physiological conditions, the main mode of metabolism in the murine neonatal heart is glycolysis, whereas that in the hearts of adult mice is fatty acid oxidation. (B) In the pathological state, glycolysis, hypoxia, NAD(P)+ synthesis, mevalonate pathway, and appropriate reduction in heart rate promote heart regeneration, while fatty acid oxidation and reactive oxygen species (ROS) inhibit myocardial regeneration in the neonatal mouse heart regeneration models (apical resection, cryoinjury, or myocardial infarction).

FIGURE 3

Major metabolic pathways and signaling pathways in heart regeneration after cardiac injury. Glucose metabolism (blue), fatty acid metabolism (purple), BCAA metabolism (orange), and biosynthetic pathways (green background). The boxed section shows the factors affecting the metabolic pathways. Wnt/β-catenin pathway and Nrg1-ErbB pathway affect the metabolism of heart regeneration. Acetyl-CoA is the final effector of these three metabolism pathways (fatty acid oxidation, glycolysis, and amino acid metabolism) and regulates the initiation of the TCA cycle. GLUT, glucose transporter type; Glucose-6-P, glucose-6-phosphate; Fructose-6-P, fructose-6-phosphate; Glyceraldehyde-3-P, glyceraldehyde-3-phosphate; PFK, phosphofructokinase; PKM2, M2-pyruvate kinase; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; CD36, cluster of differentiation; FAT, fatty acid transport carrier; CPT, carnitine palmitoyltransferase; BCAAs, branched-chain amino acids; BCAT, branched-chain amino acid transferase; BCKA, branched-chain alpha-keto acids; BCKDH, branched-chain alpha-keto acid dehydrogenase; mTOR, mammalian target of rapamycin; TCA, tricarboxylic acid cycle; SDH, succinate dehydrogenase; αKG, α-ketoglutarate; ROS, reactive oxygen species; H₂S, hydrogen sulfide; NAC, N-acetylcysteine; NAMPT, nicotinamide phosphoribosyltransferase; PAG, propargylglycine; mCAT, mitochondrial catalase; Pitx2, paired-liked homeodomain transcription factor 2; Nrf2, nuclear factor-erythroid-2-related factor 2; CDK, cyclin-dependent kinases; HBP, hexosamine biosynthesis pathway; Pck2, phosphoenolpyruvate carboxykinase 2; OGA, O-GlcNAcase. The yellow sun represents the promotion of heart regeneration, while the red lightning represents the inhibition of heart regeneration.

FIGURE 4

Venn diagram of metabolic genes associated with cardiomyocyte proliferation overlapping in different animals and cardiomyocytes. (A,B) The metabolic genes associated with cardiomyocyte proliferation in different animals (A) and cardiomyocytes (B). ACSL1, acyl-CoA synthetase long-chain family member 1; PFK, phosphofructokinase 2; PPARα, peroxisome proliferator-activated receptor; HIF-α, hypoxia-inducible factor α; PDK4, pyruvate dehydrogenase kinase 4; MEIS1, myeloid ecotropic viral integration site 1; PCK2, phosphoenolpyruvate carboxykinase 2; CPT, carnitine palmitoyltransferase; NAMPT, nicotinamide phosphoribosyltransferase; YAP, yes-associated protein; Nrg1, neuregulin 1; SDH, succinate dehydrogenase; GLUT1, glucose transporter 1; Pitx2, paired-like homeodomain 2; hiPSC-CM, human-induced pluripotent stem cell cardiomyocytes; hPSC-CM, human pluripotent stem cell-derived cardiomyocytes; P14, postnatal day 14; P21, postnatal day 21; P40, postnatal day 40.