Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-26T00:56:47.402Z Has data issue: false hasContentIssue false
  • English
  • Français

Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise

Published online by Cambridge University Press:  05 March 2007

Henriette Pilegaard  and
P. Darrell Neufer
Henriette Pilegaard*
Affiliation:
Copenhagen Muscle Research Centre, August Krogh Institute, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen Ø, Denmark
P. Darrell Neufer
Affiliation:
John B. Pierce Laboratory and Department of Cellular and Molecular Physiology, Yale University, School of Medicine, New Haven, CT 06519, USA
*
*Corresponding author: Dr Henriette Pilegaard Fax: +45 35 32 1567, Email: [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The 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.

Keywords

Pyruvate dehydrogenase kinase 4Transcriptional regulationSkeletal muscleExercise
Type
Symposium 1: Exercise signalling pathways controlling fuel oxidation during and after exercise
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 2 , May 2004 , pp. 221 - 226
Copyright
Copyright © The Nutrition Society 2004

References

Bowker-Kinley, MM, Davis, WI, Wu, P, Harris, RA & Popov, KM (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochemical Journal 329, 191–196.CrossRefGoogle ScholarPubMed
Brozinick, JT Jr, Patel, VK & Dohm, GL (1988) Effects of fasting and training on pyruvate dehydrogenase activation during exercise. International Journal of Biochemistry 20, 297–301.CrossRefGoogle ScholarPubMed
Dohm, GL, Patel, VK & Kasperek, GJ (1986) Regulation of muscle pyruvate metabolism during exercise. Biochemical Medicine and Metabolic Biology 35, 260–266.CrossRefGoogle ScholarPubMed
Furuyama, T, Kitayama, K, Yamashita, H & Mori, N (2003) Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochemical Journal 375, 365–371.CrossRefGoogle ScholarPubMed
Hagg, SA, Taylor, SI & Ruderman, NB (1976) Glucose metabolism in perfused skeletal muscle. Biochemical Journal 158, 203–210.CrossRefGoogle ScholarPubMed
Harris, RA, Huang, B & Wu, P (2001) Control of pyruvate dehydrogenase kinase gene expression. Advances in Enzyme Regulation 41, 269–288.CrossRefGoogle ScholarPubMed
Hennig, G, Löffler, G & Wieland, OH (1975) Active and inactive forms of pyruvate dehydrogenase in skeletal muscle as related to the metabolic and functional state of the muscle cell. FEBS Letters 59, 142–145.CrossRefGoogle Scholar
Hildebrandt, AL & Neufer, PD (2000) Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle. American Journal of Physiology 278, E1078–E1086.Google ScholarPubMed
Hildebrandt, AL, Pilegaard, H & Neufer, PD (2003) Differential transcriptional activation of select metabolic genes in response to variations in exercise intensity and duration. American Journal of Physiology 285, E1021–E1027.Google ScholarPubMed
Holness, MJ, Bulmer, K, Gibbons, GF & Sugden, MC (2002) Upregulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor α (PPARα). Biochemical Journal 366, 839–846.CrossRefGoogle Scholar
Holness, MJ, Kraus, A, Harris, RA & Sugden, MC (2000) Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding. Diabetes 49, 775–781.CrossRefGoogle ScholarPubMed
Mourtzakis, M, Saltin, B, Graham, T & Pilegaard, H (2002) Pyruvate dehydrogenase active form (PDHa) and carbohydrate (CHO) utilization during prolonged exercise. FASEB Journal 16, A780.Google Scholar
Muoio, DM, MacLean, PS, Lang, DB, Li, JA, Way, JM, Winegar, DA, Corton, JC, Dohm, GL & Kraus, WE (2002) Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice. Journal of Biological Chemistry 277, 26089–26097.CrossRefGoogle ScholarPubMed
Nordsborg, N, Bangsbo, J & Pilegaard, H (2003) Effect of high-intensity training on exercise-induced gene expression specific to ion homeostasis and metabolism. Journal of Applied Physiology 95, 1201–1206.CrossRefGoogle ScholarPubMed
Patel, MS & Korotchkina, LG (2001) Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases. Experimental and Molecular Medicine 33, 191–197.CrossRefGoogle ScholarPubMed
Perham, RN (2000) Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annual Review of Biochemistry 69, 961–1004.CrossRefGoogle ScholarPubMed
Peters, SJ, Harris, RA, Heigenhauser, GJ & Spriet, LL (2001 a) Muscle fiber type comparison of PDH kinase activity and isoform expression in fed and fasted rats. American Journal of Physiology 280, R661–R668.Google ScholarPubMed
Peters, SJ, Harris, RA, Wu, P, Pehleman, TL, Heigenhauser, GJ & Spriet, LL (2001 b) Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet. American Journal of Physiology 281, E1151–E1158.Google ScholarPubMed
Pilegaard, H, Helge, JW, Saltin, B & Neufer, PD (2001) Effect of substrate availability on the transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise. FASEB Journal 15, A417.Google Scholar
Pilegaard, H, Keller, C, Steensberg, A, Helge, JW, Klarlund-Petersen, B, Saltin, B & Neufer, PD (2002) Importance of glycogen content for the exercise-induced gene expression in human skeletal muscle. Journal of Physiology (London) 541, 261–271.CrossRefGoogle Scholar
Pilegaard, H, Ordway, GA, Saltin, B & Neufer, PD (2000) Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. American Journal of Physiology 279, E806–E814.Google ScholarPubMed
Pilegaard, H, Saltin, B & Neufer, PD (2003 a) Short-term fasting and re-feeding on transcriptional regulation of metabolic genes in human skeletal muscle. Diabetes 52, 657–662.CrossRefGoogle Scholar
Pilegaard, H, Van Hall, G, Sacchetti, M, Saltin, B & Neufer, PD (2003 b) Effect of free fatty acids on transcriptional regulation of metabolic genes during rest and exercise in human skeletal muscle. FASEB Journal 17, A433Abstr.Google Scholar
Putman, CT, Spriet, LL, Hultman, E, Lindinger, MI & Lands, LC (1993) Pyruvate dehydrogenase activity and acetyl group accumulation during exercise after different diets. American Journal of Physiology 265, E752–E760.Google ScholarPubMed
Reed, LJ (2001) A trail of research from lipoic acid to α-keto acid dehydrogenase complexes. Journal of Biological Chemistry 276, 38329–38336.CrossRefGoogle ScholarPubMed
Roche, TE, Baker, JC, Yan, X, Hiromasa, Y, Gong, X, Peng, T, Dong, J, Turkan, A & Kasten, SA (2001) Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Progress in Nucleic Acid Research 70, 33–75.CrossRefGoogle ScholarPubMed
Sugden, MC & Holness, MJ (2003) Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDK's. American Journal of Physiology 284, E855–E862.Google Scholar
Sugden, MC, Kraus, A, Harris, RA & Holness, MJ (2000) Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of PDK isoenzyme 4 expression. Biochemical Journal 346, 651–657.CrossRefGoogle ScholarPubMed
Ward, GR, Sutton, JR, Jones, NL & Toews, CJ (1982) Activation by exercise of human skeletal muscle pyruvate dehydrogenase in vivo. Clinical Science 63, 87–92.CrossRefGoogle ScholarPubMed
Watt, MJ, Heigenhauser, GJ, Dyck, DJ & Spriet, LL (2002) Intramuscular triacylglycerol, glycogen and acetyl group metabolism during 4 h of moderate exercise in man. Journal of Physiology (London) 541, 969–978.CrossRefGoogle Scholar
Wojtaszewski, JFP, Mourtzakis, M, Hillig, T, Saltin, B & Pilegaard, H (2002) Dissociation of AMPK activity and ACCβ phosphorylation in human muscle during prolonged exercise. Biochemical and Biophysical Research Communications 298, 309–316.CrossRefGoogle ScholarPubMed
Wu, P, Inskeep, K, Bowker-Kinley, MM, Popov, KM & Harris, RA (1999) Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 48, 1593–1599.CrossRefGoogle ScholarPubMed
Wu, P, Peters, JM & Harris, RA (2001) Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor α. Biochemical and Biophysical Research Communications 287, 391–396.CrossRefGoogle ScholarPubMed