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PDH-E1 Dephosphorylation and Activation in Human Skeletal Muscle During Exercise

Effect of Intralipid Infusion

¹ Copenhagen Muscle Research Centre, Copenhagen, Denmark
² Centre of Inflammation and Metabolism, Copenhagen, Denmark
³ Institute of Molecular Biology and Physiology, The August Krogh Building, University of Copenhagen, Copenhagen, Denmark
⁴ Department of Human Physiology, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
⁵ Rigshospitalet Section 7652, Copenhagen, Denmark
⁶ Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
⁷ Division of Molecular Physiology, School of Life Sciences, Dundeee University, Dundee, Scotland, U.K
⁸ John B. Pierce Laboratory, Cellular and Molecular Physiology, Yale University, New Haven, Connecticut

Address correspondence and reprint requests to Henriette Pilegaard, PhD, August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark. E-mail: hpilegaard{at}aki.ku.dk

Key Words: FFA, free fatty acid • PDH, pyruvate dehydrogenase • PDHa, PDH in the active form • PDH-P1, PDH-E1 site 1 • PDH-P2, PDH-E1 site 2 • PDK, PDH kinase • PDP, PDH phosphatase

To investigate pyruvate dehydrogenase (PDH)-E1 subunit phosphorylation and whether free fatty acids (FFAs) regulate PDH activity, seven subjects completed two trials: saline (control) and intralipid/heparin (intralipid). Each infusion trial consisted of a 4-h rest followed by a 3-h two-legged knee extensor exercise at moderate intensity. During the 4-h resting period, activity of PDH in the active form (PDHa) did not change in either trial, yet phosphorylation of PDH-E1 site 1 (PDH-P1) and site 2 (PDH-P2) was elevated in the intralipid compared with the control trial. PDHa activity increased during exercise similarly in the two trials. After 3 h of exercise, PDHa activity remained elevated in the intralipid trial but returned to resting levels in the control trial. Accordingly, in both trials PDH-P1 and PDH-P2 decreased during exercise, and the decrease was more marked during intralipid infusion. Phosphorylation had returned to resting levels at 3 h of exercise only in the control trial. Thus, an inverse association between PDH-E1 phosphorylation and PDHa activity exists. Short-term elevation in plasma FFA at rest increases PDH-E1 phosphorylation, but exercise overrules this effect of FFA on PDH-E1 phosphorylation leading to even greater dephosphorylation during exercise with intralipid infusion than with saline.

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