Pyruvate Kinase M2: A Potential Regulator of Cardiac Injury Through Glycolytic and Non-glycolytic Pathways

Abstract

Adult animals are unable to regenerate heart cells due to postnatal cardiomyocyte cycle arrest, leading to higher mortality rates in cardiomyopathy. However, reprogramming of energy metabolism in cardiomyocytes provides a new perspective on the contribution of glycolysis to repair, regeneration, and fibrosis after cardiac injury. Pyruvate kinase (PK) is a key enzyme in the glycolysis process. This review focuses on the glycolysis function of PKM2, although PKM1 and PKM2 both play significant roles in the process after cardiac injury. PKM2 exists in both low-activity dimer and high-activity tetramer forms. PKM2 dimers promote aerobic glycolysis but have low catalytic activity, leading to the accumulation of glycolytic intermediates. These intermediates enter the pentose phosphate pathway to promote cardiomyocyte proliferation and heart regeneration. Additionally, they activate adenosine triphosphate (ATP)-sensitive K + (K ATP ) channels, protecting the heart against ischemic damage. PKM2 tetramers function similar to PKM1 in glycolysis, promoting pyruvate oxidation and subsequently ATP generation to protect the heart from ischemic damage. They also activate KDM5 through the accumulation of αKG, thereby promoting cardiomyocyte proliferation and cardiac regeneration. Apart from glycolysis, PKM2 interacts with transcription factors like Jmjd4, RAC1, β-catenin, and hypoxia-inducible factor (HIF)-1α, playing various roles in homeostasis maintenance, remodeling, survival regulation, and neovascularization promotion. However, PKM2 has also been implicated in promoting cardiac fibrosis through mechanisms like sirtuin (SIRT) 3 deletion, TG2 expression enhancement, and activation of transforming growth factor-β1 (TGF-β1)/Smad2/3 and Jak2/Stat3 signals. Overall, PKM2 shows promising potential as a therapeutic target for promoting cardiomyocyte proliferation and cardiac regeneration and addressing cardiac fibrosis after injury.

FIGURE 1.

a, Alternative splicing of PKM1/2 is regulated by 3 heteronuclear ribonucleoprotein splicing factors: hnRNPA1, hnRNPA2, and polypyrimidine tract-binding protein (hnRNP1). Higher expression of these splicing factors inhibits the binding of exon 9 flanking sequences and the cleavage of exon 9, leading to the generation of PKM2 mRNA. By contrast, the splicing factors cleave exon 10, resulting in the formation of PKM1 mRNA. b, Tissue distribution of PKM1/2 in health and disease conditions. The figure is created with BioRender.com.

FIGURE 2.

PKM2 plays a critical role in optimizing cardiomyocyte energy after cardiac injury through glycolysis. PKM2 tetramers function similar to PKM1 in glycolysis. They promote glucose metabolism to produce pyruvate and facilitate pyruvate oxidation, ultimately leading to an increase in ATP production. Additionally, they also accumulate αKG to activate KDM5, which reduces the expression of the cardiomyocyte maturation gene H3K4me3, subsequently promoting cardiomyocyte proliferation and heart regeneration. The PKM2 dimer accumulates G-6-P into PPPs to provide survival substances for cardiomyocyte proliferation and heart regeneration. PKM2 is a multitasking regulator that interacts with different transcription factors and plays an important role in cardiomyocytes: Jmjd4 promotes the degradation of PKM2 in the myocardial cytoplasm and maintains cardiomyocyte homeostasis; PKM2 phosphorylates RAC1 to alleviate pathological cardiac remodeling under pressure overload; PKM2 interacts with β-catenin to regulate the cardiomyocyte fate; and hypoxia-inducible factor-1α promotes the expression of myocardial PKM2 and promotes neovascularization. p, phosphorylation; red ☆, promote expression. The figure is created with BioRender.com.

FIGURE 3.

After cardiac injury, PKM2 mediates the generation of cardiac fibrosis via the activation of Jak2/Stat3 and TGF-β1-Smad2/3 signaling pathways through oxidative stress, promoting extracellular matrix secretion and enhancing collagen-related gene transcription. PKM2 also promotes cardiac fibrosis by actively regulating the expression and activity of TG2, which activates TGF-β1 signaling and matrix protein synthesis through NF-κB. The loss of mitochondrial sirtuin 3 induces the hyperacetylation of ATG5, inhibits autophagosome maturation, and increases the expression of PKM2 dimers, activating TGF-β1 signaling to induce cardiac fibrosis. The figure is created with BioRender.com.