The Regulation of Pyruvate Dehydrogenase in Skeletal Muscle in Vivo and Perfused Heart

Abstract

<p>The goal was to determine the physiological significance of pyruvate dehydrogenase (PDH) activation in muscle. The PDH activity was measured in small samples of muscle obtained by needle biopsy from normal volunteers. In heart PDH was measured using an isolated perfused rat heart preparation. The PDH activity was measured by determining ¹⁴Co₂ production from pyruvate-1-¹⁴C using whole tissue homogenates.</p> <p>The total PDH (PDHt) activity in human skeletal muscle was 302 ± 10 nmol/g/min. with about 40 ± 3% in the active form (PDHa). With aerobic exercise (60% VO₂max) more than 88% of PDH was converted to PDHa within 5 min. Aerobic training did not increase the resting muscle PDHt activity (untrained 304 ± 4, trained 309 ± 8 nmol/g/min,) but it increased the PDHa from 124 ± 9 nmol/g/min. to 215 ± 15 nmol/g/min.</p> <p>Muscle immobilization by arm cast for 6 weeks decreased the PDHa from 112 ± 4 to 28 ± 4 nmol/g/min. but it had no effect on the PDHt activity. Exercise following immobilization decreased the rate and the extent of PDH activation while exercise after weight training increased the extent of PDH activation.</p> <p>Starvation for 24 and 48 hr. in rat heart decreased PDHa from 2768 ± 73 to 1286 ± 109 and 920 ± 149 nmol/g/min. respectively.</p> <p>In the perfused heart PDH was fully activated by epinephrine (1.3 μg/ml), insulin (1 mU/ml) and high (>0.2 mM) pyruvate concentration. PDH activation was not mediated by cyclic AMP since insulin activated PDH but did not change the heart cyclic AMP concentration. Propranolol prevented epinephrine from activating PDH. Octanoic acid decreased the proportion of PDH in the active form.</p> <p>In the heart a detailed study of the relationship between the rate of heart pyruvate oxidation and PDH activation was undertaken. In all experimental conditions where the rate of pyruvate oxidation was changed, parallel changes in the PDHa activity was seen. The correlation between PDH activation and rate of heart pyruvate oxidation was greater than 0.92. These findings suggest that interconversion of PDHa and PDHɨ probably control the rate of heart pyruvate oxidation. A similar correlation was not seen in skeletal muscle during exercise. The calculated rate of muscle pyruvate oxidation was several fold greater than the extent of PDH activation. Although the activation of PDH regulates pyruvate oxidation in both heart and skeletal muscle, in heart this is achieved through the interconversion of active and inactive PDH whereas in skeletal muscle allosteric conversion of the active form of PDH plays a greater part.</p>