Expression and regulation of pyruvate dehydrogenase kinase isoforms in thedeveloping rat heart and in adulthood: role of thyroid hormone status and lipid supply

Activation of the pyruvate dehydrogenase (PDH) complex (PDHC) promotes gluc ose disposal, whereas inactivation conserves glucose. The PDH kinases (PDHK s) regulate glucose oxidation through inhibitory phosphorylation of PDHC. T he adult rat heart contains three PDHK isoforms PDHK1, PDHK2 and PDHK4. Usi ng Western-blot analysis, with specific antibodies raised against individua l recombinant PDHK1, PDHK2 and PDHK4, the present study investigated PDHK i soform expression in the developing rat heart and adulthood. We identified clear differences in the patterns of protein expression of each of these PD HK isoforms during the first 3 weeks of postnatal development, with most ma rked up-regulation of isoforms PDHK1 and PDHK4. Distinctions between the th ree cardiac PDHK isoforms were also demonstrated with respect to post-neona tal maturational up-regulation; with greatest up-regulation of PDHK1 and le ast up-regulation of PDHK4 from the post-neonatal period until maturity. Th e study also examined the role of thyroid hormone status and lipid supply o n PDHK isoform expression. We observed marked selective increases in the am ount of PDHK4 protein present relative to total cardiac protein in both hyp erthyroidism and high-fat feeding. Overall, our data identify PDHK isoform PDHK1 as being of more potential regulatory importance for glucose oxidatio n in the adult compared with the neonatal heart, and cardiac PDHK4 as a PDH K isoform whose expression is specifically responsive to changes in lipid s upply, suggesting that its up-regulation during early post-natal life may b e the perinatal switch to use fatty acids as the energy source. We also ide ntify regulation of pyruvate sensitivity of cardiac PDHK as a physiological variable, a change in which requires factors in addition to a change in li pid supply.