Pyruvate dehydrogenase activation precedes the down-regulation of fatty acid oxidation in monocrotaline-induced myocardial toxicity in mice
Fatty acid (FA) oxidation is impaired and glycolysis is promoted in the damaged heart. However, the factor(s) in the early stages of myocardial metabolic impairment remain(s) unclear. C57B6 mice were subcutaneously administered monocrotaline (MCT) in doses of 0.3 mg/g body weight twice a week for 3 or 6 weeks. Right and left ventricles at 3 and 6 weeks after administration were subjected to capillary electrophoresis–mass spectrometry metabolomic analysis. We also examined mRNA and protein levels of key metabolic molecules. Although no evidence of PH and right ventricular failure was found in the MCT-administered mice by echocardiographic and histological analyzes, the expression levels of stress markers such as TNFα and IL-6 were increased in right and left ventricles even at 3 weeks, suggesting that there was myocardial damage. Metabolites in the tricarboxylic acid (TCA) cycle were decreased and those in glycolysis were increased at 6 weeks. The expression levels of FA oxidation-related factors were decreased at 6 weeks. The phosphorylation level of pyruvate dehydrogenase (PDH) was significantly decreased at 3 weeks. FA oxidation and the TCA cycle were down-regulated, whereas glycolysis was partially up-regulated by MCT-induced myocardial damage. PDH activation preceded these alterations, suggesting that PDH activation is one of the earliest events to compensate for a subtle metabolic impairment from myocardial damage.
KeywordsCardiac metabolism Metabolomics Pyruvate dehydrogenase Glycolysis Monocrotaline
This work was supported by Grants from the Ministry of Health, Labor and Welfare of Japan (S.M.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.M.), the “High-Tech Research Center” Project for Private Universities: MEXT (N.G., S.M.), the Vehicle Racing Commemorative Foundation (S.M.), and Takatomi Research Promotion Funds (Q.J.).
SM and NG conceived and designed the experiments; GN, DS, and KU performed the experiments; GN, DS, and TS analyzed the data; IK and QJ contributed reagents/materials/analysis tools; GN, DS, and SM wrote the paper.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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