PDK4 pyruvate dehydrogenase kinase, isozyme 4 polymorphismLink informatics for "PDK4 pyruvate dehydrogenase kinase, isozyme 4 polymorphism"C O N T E N T SSee Also
Descriptionchromosome: 7; Location: 7q21.3 This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. DiscussionThe pyruvate dehydrogenase complex (PDC) has a key position in skeletal muscle metabolism as it represents the entry of carbohydrate-derived fuel into the mitochondria for oxidation. PDC is regulated by a phosphorylation-dephosphorylation cycle, in which the pyruvate dehydrogenase kinase (PDK) phosphorylates and inactivates the complex. PDK exists in four isoforms, of which the PDK4 isoform is predominantly expressed in skeletal and heart muscle. PDK4 transcription and PDK4 mRNA are markedly increased in human skeletal muscle during prolonged exercise and after both short-term high-intensity and prolonged low-intensity exercise. The exercise-induced transcriptional response of PDK4 is enhanced when muscle glycogen is lowered before the exercise, and intake of a low-carbohydrate high-fat diet during recovery from exercise results in increased transcription and mRNA content of PDK4 when compared with intake of a high-carbohydrate diet. The activity of pyruvate dehydrogenase (PDH) is increased during the first 2 h of low-intensity exercise, followed by a decrease towards resting levels, which is in line with the possibility that the increased PDK4 expressed influences the PDH activity already during prolonged exercise. PDK4 expression is also increased in response to fasting and a high-fat diet. Thus, increased PDK4 expression when carbohydrate availability is low seems to contribute to the sparing of carbohydrates by preventing carbohydrate oxidation. The impact of substrate availability on PDK4 expression during recovery from exercise also underlines the high metabolic priority given to replenishing muscle glycogen stores and re-establishing intracellular homeostasis after exercise.(1) In a study where six subjects completed two trials (separated by 2 weeks) consisting of 3 h of two-legged knee extensor exercise with either control (398 +/- 52 mmol kg(-1) dry weight) or low (240 +/- 38 mmol kg(-1) dry weight) pre-exercise muscle glycogen. Exercise induced a significantly greater increase in PDK4 transcription in the low glycogen (> 6-fold) than in the control (< 3-fold) trial. Induction of PDK4 and UCP3 mRNA in response to exercise was also significantly higher in the low glycogen (11.4- and 3.5-fold, respectively) than in the control (5.0- and 1.7-fold, respectively) trial. These data indicate that low muscle glycogen content enhances the transcriptional activation of some metabolic genes in response to exercise, raising the possibility that signalling mechanisms sensitive to glycogen content and/or FFA availability may be linked to the transcriptional control of exercise-responsive genes. (2) mRNA levels of PDK4 are increased in skeletal muscle during fasting. ({Spriet LL, Tunstall RJ, Watt MJ, Mehan KA, Hargreaves M, Cameron-Smith D. Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting.J Appl Physiol. 2004 Jun;96(6):2082-7. Epub 2004 Feb 13}}) The farnesoid X receptor (FXR; NR1H4), which regulates a variety of genes involved in lipoprotein metabolism, also regulates the expression of PDK4. Treatment of mice with an FXR agonist significantly increased hepatic PDK4 expression, while concomitantly decreasing plasma triglyceride levels. Thus, activation of FXR may suppress glycolysis and enhance oxidation of fatty acids via inactivation of the PDC by increasing PDK4 expression. (3) In human muscle, hormonal and nutritional conditions may control PDK2 and PDK4 mRNA expression via a common signalling mechanism. (4) LinksReferences1. Pilegaard H, Neufer PD. Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise.Proc Nutr Soc. 2004 May;63(2):221-6. 2. Pilegaard H, Keller C, Steensberg A, Helge JW, Pedersen BK, Saltin B, Neufer PD.Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes. J Physiol. 2002 May 15;541(Pt 1):261-71. 3. Savkur RS, Bramlett KS, Michael LF, Burris TP.Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor Biochem Biophys Res Commun. 2005 Apr 1;329(1):391-6. 4. Abbot EL, McCormack JG, Reynet C, Hassall DG, Buchan KW, Yeaman SJ. Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells.: FEBS J. 2005 Jun;272(12):3004-14. |
