The Effects of Pyruvate Dehydrogenase Kinase 4 (PDK4) Inhibition on Metabolic Flexibility during Endurance Training in Skeletal Muscles of Streptozotocin-induced Diabetic Rats

• Published in: Journal of Kerman University of Medical Sciences Vol. 27; no. 4; pp. 304 - 317
• Main Authors: Hamid Marefati, Yaser Masoumi-Ardakani, Saeed Shakerian, Abdolhamid Habibi, Soheil Aminizadeh, Beydolah Shahouzehi
• Format: Journal Article
• Language: English
• Published: Kerman University of Medical Sciences 01.07.2020
• Subjects: pyruvate dehydrogenase kinase 4 endurance training metabolic flexibility estrogen; related receptor
• ISSN: 2008-2843
• DOI: 10.22062/jkmu.2020.91017

Background:Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. Pyruvate Dehydrogenase Kinase 4 (PDK4) is one of the main enzymes that play a critical role in metabolic flexibility. In current study, we examined PDK4 inhibition along with exercise training (ET) on the gene expression of Estrogen related-receptor alpha (ERRα), medium-chain acyl-CoA dehydrogenase (MCAD), carnitine palmitoyl transferase-1b (CPT-1b), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PDK4 and citrate synthase (CS) in skeletal muscle.Method:Sixty-four male Wistar rats (8 week-old) were randomly divided into 8 groups (n=8); 1- untreated control, 2- STZ-induced diabetic, 3- PDK4 inhibition, 4- endurance training (ET), 5- diabetic + PDK4 inhibition, 6- diabetic + ET, 7- PDK4 inhibition + ET, and 8- diabetic +ET + PDK4 inhibition. ERRα, MCAD, CPT-1b, PGC-1α, PDK4 and CS genes expressions were measured by Real-Time PCR and quantified by 2-ΔΔCt method.Results:ERRα, MCAD, CPT-1b, PGC-1α, PDK4, and CS expressions were significantly higher in non-diabetic+ Endurance Training group compared to the control group. The expressions of CPT-1b, MCAD and CS genes were significantly lower in the non-diabetic+ endurance training/PDK4 inhibition compared to the non-diabetic+ endurance training group, and the expressions of ERRα, CPT-1b and MCAD were significantly lower in the diabetic + PDK4 inhibition group compared to the diabetic group.Conclusion:In sum, PDK4 inhibition has negative effects on lipid metabolism in healthy rats, but in animals with diabetes, PDK4 inhibition can be used for improving lipid metabolism (over-expression of CS and PGC-1α).