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

• Published in: Iranian journal of basic medical sciences 2025-01, Vol.28 (1), p.80
• Main Authors: Rezaeinasab, Hamed, Habibi, Abdolhamid, Rezaei, Ramin, Basereh, Aref, Salva Reverentia Yurista, Khoramipour, Kayvan
• Format: Article
• Language: English
• Subjects: Dehydrogenases; Diabetes; Gene expression; Kinases; Metabolism
• ISSN: 2008-3866; 2008-3874
• DOI: 10.22038/ijbms.2024.79864.17305

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.