Ukr.Biochem.J. 2018; Volume 90, Issue 6, Nov-Dec, pp. 89-96

doi: https://doi.org/10.15407/ubj90.06.089

The effects of PDK4 inhibition on AMPK protein levels and PGC-1α gene expression following endurance training in skeletal muscle of Wistar rats

15.11.2018   Uncategorized   No comments

S. Aminizadeh1, Y. Masoumi-Ardakani1, B. Shahouzehi2

1Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Iran;
e-mail: soheilaminizadeh@gmail.com; ymab125@yahoo.com;
2Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Iran;
e-mail: bshahouzehi@gmail.com

There are regulatory networks in cells which surveil the physiological and environmental states. These cellular regulations are conducted through gene expression modulation. Skeletal muscle is able to adapt shortly and produce ATP at different conditions. AMPK (AMP-activated protein kinase) and PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) are important regulators of cellular energy homeostasis. We designed this study to examine the effects of interactions between endurance training­ and PDK4 (pyruvate dehydrogenase kinase 4) inhibition on AMPK and PGC-1α expression in rat skeletal muscle. Thirty-two male Wistar rats were randomly selected and divided into 4 groups (n = 8); Group 1 control which did not receive any treatment, Group 2 received dichloroacetic acid (DCA) (150 mg/kg/day), Group 3 (endurance training group), Group 4 which received DCA and performed endurance training. AMPK protein expression, PDK4 and PGC-1α gene expression were measured by western blotting and real-time PCR, respectively. Our data showed that PDK4 inhibition caused AMPK protein elevation. Endurance training­ (group 2) and PDK4 inhibition (group 4) induce significant enhancement of PGC-1α gene expression compared to control group. The group which received DCA showed significant elevation of PDK4 gene expression compared to control group (P = 0.001), also other two groups (groups 2 & 3) showed significant elevation of PDK4 gene expression compared to control (P = 0.006). It seems that the combination of endurance training and PDK4 inhibition by up-regulation of PGC-1α expression, effectively improves energy state and performance in skeletal muscle.

Keywords: , , , ,

References:

  1. Wende AR, Huss JM, Schaeffer PJ, Giguère V, Kelly DP. PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol. 2005 Dec;25(24):10684-94. PubMed, PubMedCentral, CrossRef
  2. Niewisch MR, Kuçi Z, Wolburg H, Sautter M, Krampen L, Deubzer B, Handgretinger R, Bruchelt G. Influence of dichloroacetate (DCA) on lactate production and oxygen consumption in neuroblastoma cells: is DCA a suitable drug for neuroblastoma therapy? Cell Physiol Biochem. 2012;29(3-4):373-80.  PubMed, CrossRef
  3. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003 Feb;24(1):78-90. PubMed, CrossRef
  4. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998 Mar 20;92(6):829-39. PubMed, CrossRef
  5. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest. 2000 Oct;106(7):847-56. PubMed, PubMedCentral, CrossRef
  6. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999 Jul 9;98(1):115-24. PubMed, CrossRef
  7. Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000 Mar;20(5):1868-76. PubMed, PubMedCentral, CrossRef
  8. Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C, Puigserver P, Spiegelman B, Montminy M. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature. 2001 Sep 13;413(6852):179-83. PubMed, CrossRef
  9. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001 Sep 13;413(6852):131-8. PubMed, CrossRef
  10. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002 Dec;16(14):1879-86. PubMed, CrossRef
  11. Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I, Shimokawa T. cDNA Cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochem Biophys Res Commun. 2000 Aug 2;274(2):350-4. PubMed, CrossRef
  12. Pilegaard H, Saltin B, Neufer PD. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol. 2003 Feb 1;546(Pt 3):851-8. PubMed, PubMedCentral, CrossRef, CrossRef
  13. Holness MJ, Kraus A, Harris RA, Sugden MC. 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. 2000 May;49(5):775-81. PubMed, CrossRef
  14. Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem. 1995 Dec 1;270(48):28989-94.  PubMed, CrossRef
  15. Wang L, Sahlin K. The effect of continuous and interval exercise on PGC-1α and PDK4 mRNA in type I and type II fibres of human skeletal muscle. Acta Physiol (Oxf). 2012 Apr;204(4):525-32. PubMed, CrossRef
  16. Huang B, Wu P, Bowker-Kinley MM, Harris RA. Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes. 2002 Feb;51(2):276-83. PubMed, CrossRef
  17. Wu P, Peters JM, Harris RA. Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha. Biochem Biophys Res Commun. 2001 Sep 21;287(2):391-6. PubMed, CrossRef
  18. Cantó C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009 Apr;20(2):98-105. PubMed, PubMedCentral, CrossRef
  19. Herbst EA, MacPherson RE, LeBlanc PJ, Roy BD, Jeoung NH, Harris RA, Peters SJ. Pyruvate dehydrogenase kinase-4 contributes to the recirculation of gluconeogenic precursors during postexercise glycogen recovery. Am J Physiol Regul Integr Comp Physiol. 2014 Jan 15;306(2):R102-7. PubMed, PubMedCentral, CrossRef
  20. Grassian AR, Metallo CM, Coloff JL, Stephanopoulos G, Brugge JS. Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 2011 Aug 15;25(16):1716-33. PubMed, PubMedCentral, CrossRef
  21. Houten SM, Chegary M, Te Brinke H, Wijnen WJ, Glatz JF, Luiken JJ, Wijburg FA, Wanders RJ. Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids. Cell Mol Life Sci. 2009 Apr;66(7):1283-94.  PubMed, CrossRef
  22. Dixit D, Ahmad F, Ghildiyal R, Joshi SD, Sen E. CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma. Exp Cell Res. 2016 May 15;344(1):132-142.  PubMed, CrossRef
  23. Sun XQ, Zhang R, Zhang HD, Yuan P, Wang XJ, Zhao QH, Wang L, Jiang R, Jan Bogaard H, Jing ZC. Reversal of right ventricular remodeling by dichloroacetate is related to inhibition of mitochondria-dependent apoptosis. Hypertens Res. 2016 May;39(5):302-11. PubMed, CrossRef
  24. Mansouri M, Nikooie R, Keshtkar A, Larijani B, Omidfar K. Effect of endurance training on retinol-binding protein 4 gene expression and its protein level in adipose tissue and the liver in diabetic rats induced by a high-fat diet and streptozotocin. J Diabetes Investig. 2014 Sep;5(5):484-91. PubMed, PubMedCentral, CrossRef
  25. Mohammadi A, Fallah H, Shahouzehi B, Najafipour H. miR-33 inhibition attenuates the effect of liver X receptor agonist T0901317 on expression of liver X receptor alpha in mice liver. ARYA Atheroscler. 2017 Nov;13(6):257-263. PubMed, PubMedCentral
  26. Lanvin O, Bianco S, Kersual N, Chalbos D, Vanacker JM. Potentiation of ICI182,780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790. J Biol Chem. 2007 Sep 28;282(39):28328-34. PubMed, CrossRef
  27. Zhou X, Yu S, Su J, Sun L. Computational Study on New Natural Compound Inhibitors of Pyruvate Dehydrogenase Kinases. Int J Mol Sci. 2016 Mar 4;17(3):340. PubMed, PubMedCentral, CrossRef
  28. Fritzen AM, Lundsgaard AM, Jeppesen J, Christiansen ML, Biensø R, Dyck JR, Pilegaard H, Kiens B. 5′-AMP activated protein kinase α2 controls substrate metabolism during post-exercise recovery via regulation of pyruvate dehydrogenase kinase 4. J Physiol. 2015 Nov 1;593(21):4765-80. PubMed, PubMedCentral, CrossRef
  29. Zhou X, Wu W, Chen J, Wang X, Wang Y. AMP-activated protein kinase is required for the anti-adipogenic effects of alpha-linolenic acid. Nutr Metab (Lond). 2015 Mar 8;12:10. PubMed, PubMedCentral, CrossRef
  30. Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999 Aug;48(8):1667-71. PubMed, CrossRef
  31. Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA. 2007 Jul 17;104(29):12017-22. PubMed, PubMedCentral, CrossRef
  32. Brandt N, Dethlefsen MM, Bangsbo J, Pilegaard H. PGC-1α and exercise intensity dependent adaptations in mouse skeletal muscle. PLoS One. 2017 Oct 19;12(10):e0185993.
    PubMed, PubMedCentral, CrossRef
  33. Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem J. 2009 Mar 1;418(2):261-75. PubMed, PubMedCentral, CrossRef
  34. Trewin AJ, Berry BJ, Wojtovich AP. Exercise and Mitochondrial Dynamics: Keeping in Shape with ROS and AMPK. Antioxidants (Basel). 2018 Jan 6;7(1). pii: E7. PubMed, PubMedCentral, CrossRef
  35. Brandauer J, Andersen MA, Kellezi H, Risis S, Frøsig C, Vienberg SG, Treebak JT. AMP-activated protein kinase controls exercise training- and AICAR-induced increases in SIRT3 and MnSOD. Front Physiol. 2015 Mar 24;6:85. PubMed, PubMedCentral, CrossRef
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