Endurance training and pyruvate dehydrogenase kinase ۴ (PDK۴) inhibition combination is superior to each one alone in attenuating hyperketonemia/ketoacidosis in diabetic rats

Objective(s): While ketone bodies are not the main heart fuel, exercise may increase their uptake. This study aimed to investigate the effect of ۶-week endurance training and Pyruvate dehydrogenase kinase ۴ )PDK۴( inhibition on ketone bodies metabolism in the heart of diabetic rats with emphasis on the role of Peroxisome proliferator-activated receptor-gamma coactivator PGC-۱alpha (PGC-۱α).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 (۳۰–۵۰ min running at ۲۰–۳۰ 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 ۶-week endurance training increased the cardiac expression of PGC-۱α, ۳-oxoacid CoA-transferase ۱ (OXCT۱), and Acetyl-CoA Acetyltransferase ۱ (ACAT۱) and reduced beta-hydroxybutyrate dehydrogenase۱ (BDH۱) expression (P≤۰.۰۵). In addition, exercise and DCA usage significantly decreased PDK۴ gene expression, ßOHB, and AcAc blood levels (P≤۰.۰۵). Furthermore, the combination of ۶-week endurance training and DCA supplementation led to more reduction in PDFK۴ 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.

کلیدواژه ها:

Dietary supplements ، Endurance training ، Gene expression ، Ketone bodies ، ketosis ، Pyruvate dehydrogenase - kinase ۴