HUMAN SKELETAL MUSCLE PDH KINASE ACTIVITY INCREASES DURING PROLONGED EXERCISE

Abstract

During prolonged sub-maximal exercise, there is a shift in skeletal muscle substrate utilization from carbohydrate to fat oxidation. This decrease in carbohydrate oxidation is due at least in part to decreased activity of the active form of pyruvate dehydrogenase (PDHa). However, the exact mechanism of the observed decrease in PDHa activity is unknown. PDHa is down-regulated by an intrinsic PDH kinase (PDK) which can either be up-regulated acutely by allosteric effectors, or in an chronic manner which is independent of changes in mitochondrial effectors. PURPOSE To test the hypothesis that the observed decrease in PDHa activity during a single 4 h exercise bout is due to a chronic increase in PDK activity. METHODS Healthy male volunteers (n = 7; age, 24 ± 4 yr; mean maximal oxygen uptake or VO2max, 53.1 ± 1.6 ml/kg/min) were asked to cycle at 55% of their VO2max for 4 hours. At 0 min, 10 min, and 4 h two biopsies were taken. One biopsy was frozen immediately in liquid nitrogen for analysis of PDHa activity. A second biopsy was extracted fresh for intact mitochondria and subsequent PDK activity (calculated as the first-order rate constant of PDHa inactivation, min−1). Respiratory exchange ratio (RER) was used to calculate energy contributions from carbohydrate and fat oxidation. RESULTS RER decreased during exercise from 0.94 ± 0.01 to 0.79 ± 0.01, carbohydrate oxidation decreased from 35 ± 3 to 12.0± 1.5 kJ/min, and fat oxidation increased from 8.3 ± 0.8 to 30.2 ± 1.2 g/min. PDHa activity increased from 0 to 10 min, but was decreased at 4 h (0.79 ± 0.08, 2.86 ± 0.26, and 2.23 ± 0.24 respectively). PDK activity was increased ∼2 fold by 4 h (0 min, 0.077 ± 0.016; 10 min, 0.119 ± 0.016 and 4 h, 0.173 ± 0.019 min−1). CONCLUSION Decreased PDHa activity while cycling at 55% VO2max for 4 h is associated with a chronic increase in PDK activity. Supported by NSERC and CIHR, Canada