Abstract
The pyruvate dehydrogenase complex (PDC) is a key control point of energy metabolism and is subject to regulation by multiple mechanisms, including posttranslational phosphorylation by pyruvate dehydrogenase kinase (PDK). Pharmacological modulation of PDC activity could provide a new treatment for diabetic cardiomyopathy, as dysregulated substrate selection is concomitant with decreased heart function. Dichloroacetate (DCA), a classic PDK inhibitor, has been used to treat diabetic cardiomyopathy, but the lack of specificity and side effects of DCA indicate a more specific inhibitor of PDK is needed. This study was designed to determine the effects of a novel and highly selective PDK inhibitor, 2((2,4-dihydroxyphenyl)sulfonyl) isoindoline-4,6-diol (designated PS10), on pyruvate oxidation in diet-induced obese (DIO) mouse hearts compared with DCA-treated hearts. Four groups of mice were studied: lean control, DIO, DIO + DCA, and DIO + PS10. Both DCA and PS10 improved glucose tolerance in the intact animal. Pyruvate metabolism was studied in perfused hearts supplied with physiological mixtures of long chain fatty acids, lactate, and pyruvate. Analysis was performed using conventional 1H and 13C isotopomer methods in combination with hyperpolarized [1-13C]pyruvate in the same hearts. PS10 and DCA both stimulated flux through PDC as measured by the appearance of hyperpolarized [13C]bicarbonate. DCA but not PS10 increased hyperpolarized [1-13C]lactate production. Total carbohydrate oxidation was reduced in DIO mouse hearts but increased by DCA and PS10, the latter doing so without increasing lactate production. The present results suggest that PS10 is a more suitable PDK inhibitor for treatment of diabetic cardiomyopathy.
Highlights
The present results suggest that PS10 is a more suitable pyruvate dehydrogenase kinase (PDK) inhibitor for treatment of diabetic cardiomyopathy
We compared effects of single-dose PDK inhibitors on the pyruvate dehydrogenase complex (PDC) activity in heart at the doses mentioned above. Treatment with both PDK inhibitors resulted in significant enhancements of PDC activity in diet-induced obese (DIO) mouse hearts compared with DIO controls (Fig. 1B)
The elevated PDC activity by both PDK inhibitors corresponded to a decrease of phosphorylation on the PDC E1␣ subunit in DIO mouse hearts (Fig. 1C)
Summary
To compare the metabolic effects of each PDK inhibitor, we first assayed the optimal dose of each agent for restoration of glucose tolerance in DIO mice after 2 weeks of treatment. PDK inhibitors, PS10 (Fig. 2C) and DCA (Fig. 2D), restored the [13C]bicarbonate signal in DIO hearts to levels higher than that in the lean control. It is clear that both the C4 quartet and D45 are stronger in the DIO control group, with decreased pyruvate anaplerosis in the DCA-treated hearts as evidenced by the increased fraction of C4Q (Fig. 4C). The carbohydrate contribution to the total acetyl-CoA pool was smaller in the DCA group than the PS10 group (Fig. 5A), whereas the fatty acid contribution was not suppressed in the DCA group compared with the PS10 group (Fig. 5B) These results indicate that under our non–steady state experimental conditions, PS10 efficiently modulated PDC activity, whereas DCA did not. S4 and S5 showed data similar to those obtained in the glutamate, but in this analysis the fractional contribution of carbohydrates to total TCA flux was significantly raised in the case of PS10 (Fig. S5D)
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