Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice

Abstract

MS.Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice. Am J Physiol Heart Circ Physiol 295: H946 -H952, 2008. First published June 27, 2008 doi:10.1152/ajpheart.00363.2008.-Pyruvate dehydrogenase complex (PDC) plays an important role in energy homeostasis in the heart by catalyzing the oxidative decarboxylation of pyruvate derived primarily from glucose and lactate. Because various pathophysiological states can markedly alter cardiac glucose metabolism and PDC has been shown to be altered in response to chronic ischemia, cardiac physiology of a mouse model with knockout of the ␣-subunit of the pyruvate dehydrogenase component of PDC in heart/skeletal muscle (H/SM-PDCKO) was investigated. H/SM-PDCKO mice did not show embryonic lethality and grew normally during the preweaning period. Heart and skeletal muscle of homozygous male mice had very low PDC activity (ϳ5% of wild-type), and PDC activity in these tissues from heterozygous females was ϳ50%. Male mice did not survive for Ͼ7 days after weaning on a rodent chow diet. However, they survived on a high-fat diet and developed left ventricular hypertrophy and reduced left ventricular systolic function compared with wild-type male mice. The changes in the heterozygote female mice were of lesser severity. The deficiency of PDC in H/SM-PDCKO male mice greatly compromises the ability of the heart to oxidize glucose for the generation of energy (and hence cardiac function) and results in cardiac pathological changes. This mouse model demonstrates the importance of glucose oxidation in cardiac energetics and function under basal conditions. Pdha1 gene deletion; ventricular hypertrophy; high fat diet; sudden death THE HEALTHY ADULT MAMMALIAN heart derives 60 -90% of ATP from fatty acid oxidation, 10 -40% from glucose and lactate oxidation in the tricarboxylic acid (TCA) cycle [through the pyruvate dehydrogenase (PDH) complex (PDC)], and Ͻ2% from glycolysis (9,21,22). The pathways of uptake and oxidation of fatty acids and glucose are tightly regulated because the heart has limited storage capacity for fatty acids and glucose, and it needs to respond to the changes in fuel availability and energy demands. The switch in the fuel selection provides for constant ATP production despite different developmental, dietary, and pathophysiological conditions. For example, the fetal heart relies more on glucose metabolism, whereas fatty acid oxidation is the primary energy source for the adult heart (15). Different pathological conditions such as cardiac hypertrophy, hypoxia, and ischemia change cardiac metabolism toward glucose utilization, whereas diabetes shifts metabolism toward fatty acid oxidation. Exercise and fasting conditions also lead to increases in fatty acid oxidation and decreases in glucose oxidation (9,21,22).PDC plays a key role in glucose metabolism by linking glycolysis and the TCA cycle. PDC is a highly organized multienzyme complex composed of three catalytic components (PDH, dihydrolipoamid...

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