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Effects of Endurance Exercise Training on Insulin Signaling in Human Skeletal Muscle

Interactions at the Level of Phosphatidylinositol 3-Kinase, Akt, and AS160

From the Copenhagen Muscle Research Centre, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark

Address correspondence and reprint requests to Jørgen F.P. Wojtaszewski, Copenhagen Muscle Research Centre, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, 13, Universitetsparken, DK-2100, Copenhagen, Denmark. E-mail: jwojtaszewski{at}ifi.ku.dk

Abbreviations: aPKC, atypical protein kinase C; GS, glycogen synthase; GSK, glycogen synthase kinase; HK2, hexose kinase 2; IRAP, insulin-responsive aminopeptidase; IR, insulin receptor; IRS-1, insulin receptor substrate-1; PI3-K, phosphatidylinositol 3-kinase; PWL, peak work load; SNAP, soluble N-ethylmaleimide–sensitive factor attachment protein; SNARE, soluble N-ethylmaleimide–sensitive factor attachment protein receptor

The purpose of this study was to investigate the mechanisms explaining improved insulin-stimulated glucose uptake after exercise training in human skeletal muscle. Eight healthy men performed 3 weeks of one-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was 60% higher (P < 0.01) in the trained compared with the untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies were obtained before and after training as well as after 10 and 120 min of insulin stimulation in both legs. Protein content of Akt1/2 (55 ± 17%, P < 0.05), AS160 (25 ± 8%, P = 0.08), GLUT4 (52 ± 19%, P < 0.001), hexokinase 2 (HK2) (197 ± 40%, P < 0.001), and insulin-responsive aminopeptidase (65 ± 15%, P < 0.001) increased in muscle in response to training. During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)–associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P < 0.005), and glycogen synthase (GS) (percent I-form, P < 0.05) increased similarly in both trained and untrained muscle, consistent with increased phosphorylation of Akt Thr³⁰⁸, Akt Ser⁴⁷³, AS160, glycogen synthase kinase (GSK)-3 Ser²¹, and GSK-3ß Ser⁹ and decreased phosphorylation of GS site 3a+b (all P < 0.005). Interestingly, training improved insulin action on thigh blood flow, and, furthermore, in both basal and insulin-stimulated muscle tissue, activities of Akt1 and GS and phosphorylation of AS160 increased with training (all P < 0.05). In contrast, training reduced IRS-1–associated PI3-K activity (P < 0.05) in both basal and insulin-stimulated muscle tissue. Our findings do not support generally improved insulin signaling after endurance training; rather it seems that improved insulin-stimulated glucose uptake may result from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism.

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