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

Abstract

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 ϳ60% 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 Thr 308 , Akt Ser 473 , AS160, glycogen synthase kinase (GSK)-3␣ Ser 21 , and GSK-3␤ Ser 9 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.

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

“…The training-induced improvement in glucose disposal has been attributed, at least in part, to increased insulin-stimulated glucose storage and GS fractional velocity, which correlated with insulin-stimulated glucose storage (119). Dela et al (152) also noted increases in nonoxidative glucose disposal associated with increased GS mRNA and Frosig et al (211) noted increased GS activity with short-term training. Ferrara et al (195) noted similar effects on GS fractional activity in response to insulin, with no change in total activity.…”

Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle

“…T649A knockin mice are insulin resistant [35], suggesting that pT649-TBC1D4 is more important for insulin-stimulated vs contraction-stimulated glucose uptake. Electroporation of mouse TA with WT TBC1D4 reduced contraction-stimulated glucose uptake, and there was a further ~20–25% deficit of contraction-stimulated glucose uptake for muscles transfected with the 4P-TBC1D4 mutant, suggesting the TBC1D4 phosphorylation may influence contraction-stimulated glucose uptake [34, 63, 64]. The explanation for the differing results of the 4PTBC1D4 model vs the T649A knockin model on contraction-stimulated glucose uptake is uncertain, but may relate to the six- to eightfold overexpression of TBC1D4 in the 4P-TBC1D4 model, and/or the mutations of three additional phosphomotifs (including S588) in 4P-TBC1D4.…”

Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training

“…Increased expression and activity/phosphorylation of Akt and AS160 were also evident after training. However, the sequence leading from Akt activation to GS activation in skeletal muscle was not affected by endurance training, suggesting that Akt1 is not a major kinase regulating GS in human skeletal muscle in response to insulin stimulation (Frøsig et al 2007).…”

“…Insulin signaling stimulates the non-oxidative glucose metabolism involving GS activation, the rate-limiting enzyme in the storage of glucose in glycogen particles (Roach 2002). It has been reported that, in response to 3 weeks of onelegged endurance exercise training, insulin-stimulated glucose uptake markedly increased in trained compared with untrained muscle (Frøsig et al 2007). This increase coincided with an increase in protein expression of GLUT4, and HK II, as well as increased GS total activity in skeletal muscle.…”

“…This increase coincided with an increase in protein expression of GLUT4, and HK II, as well as increased GS total activity in skeletal muscle. These adaptations are likely able to improve the intracellular conditions for uptake and metabolism of glucose (Frøsig et al 2007). Increased expression and activity/phosphorylation of Akt and AS160 were also evident after training.…”