Regulation of Cardiac Metabolism and Inflammation by Pyruvate Kinase Muscle Isoform 2
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2024
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The metabolic pathways in the heart are fine-tuned to supply substantial amounts of energy for contraction. Metabolic dysfunction not only diminishes energy production but can also enhance oxidative stress. Pyruvate kinase (muscle isoform 2, PKM2), a glycolytic enzyme, has emerged as a potentially cardioprotective therapeutic target to reduce oxidative stress. Its physiological role in the healthy heart remains to be explored. Using germline PKM2 knockout mice (PKM2-/-), we characterized the metabolic functions of PKM2 in the heart. Glucose isotopic tracing revealed perturbations in glucose flux that prioritized glucose consumption in lipid synthesis and the pentose phosphate pathway in PKM2-/- cardiomyocytes compared to controls. Removal of PKM2 altered lipid profiles, led to the accumulation of lipid droplets, and impaired insulin-mediated glucose uptake in cardiomyocytes. These alterations impaired mitochondrial respiration, increased mitochondrial superoxide production in cardiomyocytes, and depleted ATP in PKM2-/- hearts. Our study establishes PKM2 as a metabolic regulator of oxidative stress in the healthy heart. We also provide evidence of enhanced cardiac and systemic inflammation in PKM2-/- mice. In addition, PKM2-/- hearts exhibited aggravated fibrosis following myocardial infarction.
Our study demonstrates important roles for PKM2 in the unstressed heart in regulating energy production, oxidative stress, and cardiac inflammation. These functions carry over to the stressed heart and reveal PKM2 as a cardioprotective enzyme in limiting cardiac remodeling after infarction.
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Cellular biology, glucose, myocardial infarction, oxidative stress, pyruvate kinase
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209 pages
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