Endurance training and pyruvate dehydrogenase kinase 4 (PDK4) inhibition combination is superior to each one alone in attenuating hyperketonemia/ketoacidosis in diabetic rats

Document Type : Original Article

Authors

1 Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Shahid Chamran University, Ahvaz, Iran

2 Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran

3 Head of Research and Development Department, Islamic Republic of Iran Basketball Federation

4 Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran

5 Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA

6 i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012 Valladolid, Spain

10.22038/ijbms.2024.79864.17305

Abstract

Objective(s): While ketone bodies are not the main heart fuel, exercise may increase their uptake. This study aimed to investigate the effect of 6-week endurance training and Pyruvate dehydrogenase kinase 4 )PDK4( inhibition on ketone bodies metabolism in the heart of diabetic rats with emphasis on the role of Peroxisome proliferator-activated receptor-gamma coactivator PGC-1alpha (PGC-1α).
Materials and Methods: Sixty male Wistar rats were divided into eight groups: healthy control group (CONT), endurance training group (TRA), diabetic group (DM), DM + EX group, Dichloroacetate (DCA) group, DM + DCA group, TRA + DCA group, and DM + TRA + DCA group. Diabetes was induced using streptozotocin (STZ). The animals in training groups ran on the treadmill for six weeks (30–50 min running at 20–30 m/min). After the training period, molecular markers for mitochondrial biogenesis and ketone metabolism were assessed in the heart. Circulating ß-hydroxybutyrate (ßOHB) and Acetylacetonate (AcAc) levels were also measured. 
Results: Our results showed that 6-week endurance training increased the cardiac expression of PGC-1α, 3-oxoacid CoA-transferase 1 (OXCT1), and Acetyl-CoA Acetyltransferase 1 (ACAT1) and reduced beta-hydroxybutyrate dehydrogenase1 (BDH1) expression (P≤0.05). In addition, exercise and DCA usage significantly decreased PDK4 gene expression, ßOHB, and AcAc blood levels (P≤0.05). Furthermore, the combination of 6-week endurance training and DCA supplementation led to more reduction in PDFK4 gene expression, ßOHB, and AcAc blood levels. 
Conclusion: Six-week endurance training and DCA supplementation could safely improve ketone body metabolism in the heart, ultimately reducing hyperketonemia/ketoacidosis in diabetic rats. 

Keywords

Main Subjects

References

1. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 2013; 304:H1060-H1076.
2. Shafqat N, Kavanagh KL, Sass JO, Christensen E, Fukao T, Lee Wh et al. A structural mapping of mutations causing succinyl-CoA: 3-ketoacid CoA transferase (SCOT) deficiency. J Inherit Metab Dis 2013; 36:983-987.
3. Cotter DG, d’Avignon DA, Wentz AE, Weber ML, Crawford PA. Obligate role for ketone body oxidation in neonatal metabolic homeostasis. J Biol Chem 2011; 286:6902-6210.
4. Little JP, Safdar A, Wilkin GP, Tarnopolsky MA, Gibala MJ. A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. J Physiol 2010; 588:1011-1022.
5. Svensson K, Albert V, Cardel B, Salatino S, Handschin C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J 2016;30:1976-1986.
6. Whitehouse S, Randle PJ. Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate (Short Communication). Biochem J 1973; 134:651-653.
7. Škorja Milić N, Dolinar K, Miš K, Matkovič U, Bizjak M, Pavlin M, et al. Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α. Int J Mol Sci 2021; 22:8610-8635.
8. Katayama Y, Kawata Y, Moritoh Y, Watanabe M. Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, ameliorates type 2 diabetes via reduced gluconeogenesis. Heliyon 2022; 8:e08889.
9. Song X, Liu J, Kuang F, Chen X, Zeh HJ 3rd, Kang R, et al. PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. Cell Rep 2021; 34:108767.
10. McAinch AJ, Cornall LM, Watts R, Hryciw DH, O’Brien PE, Cameron-Smith D. Increased pyruvate dehydrogenase kinase expression in cultured myotubes from obese and diabetic individuals. Eur J Nutr 2015; 54:1033-1043.
11. Orumiyehei A, Khoramipour K, Rezaei MH, Madadizadeh E, Meymandi MS, Mohammadi F, et al. High-intensity interval training-induced hippocampal molecular changes associated with improvement in anxiety-like behavior but not cognitive function in rats with type 2 diabetes. Brain Sci 2022; 12:1280-1292.
12. Stacpoole PW. Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. J Natl Cancer Inst 2017; 109:1-14.
13. Thomas C, Perrey S, Lambert K, Hugon G, Mornet D, Mercier J. Monocarboxylate transporters, blood lactate removal after supramaximal exercise, and fatigue indexes in humans. J Appl Physiol 2005; 98:804-809.
14. Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis 2015; 38:895-904.
15. Sun L, Shen W, Liu Z, Guan S, Liu J, Ding S. Endurance exercise causes mitochondrial and oxidative stress in rat liver: Effects of a combination of mitochondrial targeting nutrients. Life Sci 2010; 86:39-44.
16. Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, et al. American heart association council on basic cardiovascular sciences. assessing cardiac metabolism: A scientific statement from the american heart association. Circ Res 2016; 118:1659-1701.
17. Rami M, Rahdar S, Azimpour M, Khoramipour K. The effect of high intensity interval training (HIIT) on PI3K-AKT-FOXO3 protein content in heart muscle of type 2 diabetic model rats. JPSBS 2023; 11:8-21.
18. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007; 115:3213-3223.
19. Brahma MK, Wende AR, McCommis KS. CrossTalk opposing view: Ketone bodies are not an important metabolic fuel for the heart. J Physiol 2022; 600:1005-1007.
20. Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Shono M, Kugimiya F, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism 2017; 77:65-72.
21. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, et al. The failing heart relies on ketone bodies as a fuel. Circulation 2016; 133:698-705.
22. Cheng CF, Ku HC, Lin H. PGC-1α as a pivotal factor in lipid and metabolic regulation. Int J Mol Sci 2018; 19:3447-3467.
23. Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem J 2009; 418:261-275.
24. Czubryt MP, Olson EN. Balancing contractility and energy production: The role of myocyte enhancer factor 2 (MEF2) in cardiac hypertrophy. Recent Prog Horm Res 2004; 59:105-124.
25. 1.    Puchalska P, Crawford PA. Metabolic and signaling roles of ketone bodies in health and disease. Annual review of nutrition. 2021; 41:49-77.
26. Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol 2017; 595:2857-2871.
27. Hoshino D, Tamura Y, Masuda H, Matsunaga Y, Hatta H. Effects of decreased lactate accumulation after dichloroacetate administration on exercise training-induced mitochondrial adaptations in mouse skeletal muscle. Physiol Rep 2015; 3:e12555.
28. James MO, Jahn SC, Zhong G, Smeltz MG, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther 2017; 170:166-180.
29. Hansen ESS, Bertelsen LB, Bøgh N, Miller J, Wohlfart P, Ringgaard S, et al. Concentration-dependent effects of dichloroacetate in type 2 diabetic hearts assessed by hyperpolarized [1-13 C]-pyruvate magnetic resonance imaging. NMR Biomed 2022; 35:e4678.
30. Le Page LM, Rider OJ, Lewis AJ, Ball V, Clarke K, Johansson E, et al. Increasing pyruvate dehydrogenase flux as a treatment for diabetic cardiomyopathy: A combined 13C hyperpolarized magnetic resonance and echocardiography study. Diabetes 2015; 64:2735-2743. 
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 1
January 2025
Pages 80-86

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