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|Title:||Regulation of Pyruvate Dehydrogenase Activity In Human Skeletal Muscle|
|Authors:||Putman, Theodore Charles|
|Department:||Medical Sciences, Division of Physiology/Pharmacology|
|Keywords:||Medical Pharmacology;Medical Physiology;Medical Pharmacology|
|Abstract:||<p>Regulation of the flux-generating enzyme complex pyruvate dehydrogenase (PDHc) was examined in the context of its physiological function in human skeletal muscle. In the first two studies, the role of PDHc in intramuscular fuel selection and the mechanisms regulating PDHc transformation from its inactive form (PDHb) to its active form (PDHa) and PDHa activity were examined. In a third study, the role of PDHc in muscle lactate production during exercise and recovery was assessed and the factors controlling transformation to PDHa were also examined.</p> <p>In the first study, 5 subjects were examined during rest and cycling exercise at 75% of VO₂max after 3 days of consuming a low-carbohydrate (LCD) or high-carbohydrate (RCD) diet In the second study, 8 subjects were examined at rest and during cycling exercise at 40% and 80% VO₂max while they were infused with sodium acetate (ACE) or sodium bicarbonate (BIC). At rest, consumption of a LCD and ACE infusion increased the intramuscular acetylCoA-to-CoASH ratio and citrate, as a result of increased oxidation of available fat fuels and acetate, respectively. Elevation of the acetylCoA-to-CoASH ratio and citrate inhibited PDHa and phosphofructokinase activity, respectively. Consequently, the rates of pyruvate oxidation by PDHa and pyruvate production by glycolysis were reduced preventing the oxidation of intramuscular glucose. The resting results of these two studies were consistent with the operation of a reciprocal cycle of glucose and fat oxidation for intramuscular energy production. The events leading to glucose restriction were initiated by changes in acetylCoA accumulation which caused an increase in the acetylCoA-to-CoASH ratio and citrate concentration which induced the transformation of PDHa to PDHb and inhibition of glycolytic flux, respectively.</p> <p>In contrast, during exercise at 40%, 75% and 80% VO₂max, transformation from PDHb to PDHa was determined by Ca²⁺ and was not restricted in any of the conditions except the LCD condition. Lower PDHa activity and incomplete transformation to PDHa occurred in this condition, placing a restriction on intramuscular glucose utilization. However, the acetylCoA-to-CoASH ratio actually decreased in this condition, suggesting that the lower rate of transformation was independent of alterations in the acetylCoA-to-CoASH ratio. In contrast, when transformation to PDHa was not limited in any other condition there was an increase in the acetylCoA-to-CoASH ratio which should have limited transformation. Thus, during exercise, the restriction on muscle glucose oxidation occurred only after a LCD indicating that this reciprocal cycle of fuel selection and utilization was also operating during exercise and that PDHc transformation was an integral part of its operation. However, during exercise, the regulatory factors controlling PDHa differed from those that determined the activity of this enzyme at rest. Lower PDHa during exercise in the LCD condition was consistent with an increase in the PDH-kinase/PDH-phosphatase activity ratio, in the 3 day period before exercise, increasing the occupancy of monophosphate esters on both the transformation site and the inhibitory sites of the Elα components. Incomplete removal of these additional phosphate esters by PDH-phosphatase during exercise may have then resulted in lower PDHa and glucose conservation later on during exercise.</p> <p>In a third study, the role of PDHa in muscle lactate production during exercise and recovery was examined and the factors controlling PDHc transformation were determined in 7 subjects. During repeated 30 second bouts of maximal isokinetic cycling exercise, complete transformation to PDHa occurred concurrently with muscle lactate accumulation and increased mitochondrial oxidation, indicating that lactate production was not dependent on the development of tissue hypoxia. Instead, during exercise muscle lactate production resulted from a rate of glycolytic pyruvate production that was greater than PDHa activity. Conversely, during recovery, net lactate oxidation occurred as the lactate dehydrogenase equilibrium shifted more toward pyruvate production and PDHa remained partially active due to attenuation of the acetylCoA-to-CoASH ratio, reductions in the ratios of NADH-to-NAD and ATP-to-ADP and elevated concentrations of hydrogen ion and pyruvate.</p> <p>The present studies extend the analysis of PDHc regulation from in vitro and in situ studies to human skeletal muscle in vivo. The findings of the present studies suggest that the during muscle contraction the most important factor regulating PDHc transformation in human muscle is probably Ca⁺, while the other regulatory factors perform secondary roles. In contrast, during rest and recovery from maximal exercise, PDHc transformation to PDHa and PDHa activity are determined by the intramuscular ratios of acetyICoA-to-CoASH, NADH-to-NAD, ATP-to-ADP and the concentrations of hydrogen ion and pyruvate.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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