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Investigating Cardiac Metabolism in the Isolated Perfused Mouse Heart with Hyperpolarized [1-13C]Pyruvate and 13C/31P NMR Spectroscopy
Published on: April 21, 2023
Pyruvate Kinase M2: A Potential Regulator of Cardiac Injury Through Glycolytic and Non-glycolytic Pathways
Chenxin Zeng1,2, Jiangfeng Wu1,3, Junming Li1,2
1The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China.
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.
Insights
Pyruvate kinase M2 (PKM2) plays a dual role in heart repair. Its dimeric form aids regeneration by promoting glycolysis and pentose phosphate pathway activity, while its tetrameric form supports energy production and cardiac regeneration.
Area of Science:
- Cardiovascular Biology
- Metabolic Regulation
- Regenerative Medicine
Background:
- Adult heart regeneration is limited by cardiomyocyte cell cycle arrest, increasing cardiomyopathy mortality.
- Metabolic reprogramming, particularly glycolysis, is crucial for cardiac repair, regeneration, and fibrosis.
- Pyruvate kinase (PK) is a key glycolytic enzyme, with PKM1 and PKM2 isoforms having significant roles post-cardiac injury.
Purpose of the Study:
- To review the multifaceted role of Pyruvate Kinase M2 (PKM2) in cardiac injury response.
- To elucidate PKM2's function in glycolysis, cardiomyocyte proliferation, and cardiac regeneration.
- To explore PKM2's involvement in both protective and detrimental cardiac remodeling processes, including fibrosis.
Main Methods:
- Review of existing literature on PKM2 function in the heart.
- Analysis of PKM2's enzymatic activity (dimer vs. tetramer) and its downstream effects.
- Investigation of PKM2 interactions with other signaling molecules and transcription factors.
Main Results:
- PKM2 exists as a dimer (promoting aerobic glycolysis, pentose phosphate pathway, and regeneration) and a tetramer (supporting ATP production and regeneration via KDM5).
- PKM2 dimers facilitate cardiomyocyte proliferation and protect against ischemic damage by activating K ATP channels.
- PKM2 tetramers promote ATP generation and cardiac regeneration, while PKM2 also interacts with various factors influencing cardiac homeostasis and neovascularization.
- Conversely, PKM2 is implicated in cardiac fibrosis through mechanisms involving SIRT3, TG2, TGF-β1/Smad2/3, and Jak2/Stat3 signaling.
Conclusions:
- PKM2 exhibits a complex, context-dependent role in cardiac injury, promoting regeneration and protection in one form and potentially fibrosis in another.
- Targeting PKM2 offers therapeutic potential for enhancing cardiomyocyte proliferation and cardiac regeneration while mitigating fibrosis.
- Understanding PKM2's dual functions is critical for developing effective strategies for heart repair.
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