Akt Substrate of 160 kDa Dephosphorylation Rate Is Reduced in Insulin-Stimulated Rat Skeletal Muscle After Acute Exercise

Arias, Edward B.; Wang, H; Cartee, Gregory D.

doi:10.33549/physiolres.933591

Cited by 9 publications

(14 citation statements)

References 11 publications

(27 reference statements)

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“…However, when a TBC1D4-Ser711Ala mutant is overexpressed in skeletal muscle by gene electrotransfer, the ability of insulin to enhance phosphorylation of TBC1D4-Thr649 is impaired (14), suggesting that Ser711 phosphorylation increases the potential of upstream kinase Akt to phosphorylate TBC1D4. This seemingly increased effect of Akt on TBC1D4 several hours after prior AMPK activation by AICAR and contraction may be mediated by altered cellular localization of TBC1D4 and/or a decreased ability of phosphatases to dephosphorylate TBC1D4 during submaximal insulin concentrations (24,25). Taken together, our observations may suggest that activation of AMPK in some way primes TBC1D4 for a subsequent insulin stimulus, which leads to enhanced insulin-stimulated glucose uptake.…”

Section: Discussionmentioning

confidence: 65%

TBC1D4 Is Necessary for Enhancing Muscle Insulin Sensitivity in Response to AICAR and Contraction

et al. 2019

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Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. We recently demonstrated that AMPK is necessary for AICAR, contraction, and exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization. However, the necessity of TBC1D4 for this phenomenon has not been proven. Thus, the purpose of this study was to determine whether TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. We found that immediately after contraction and AICAR stimulation, phosphorylation of AMPKα-Thr172 and downstream targets were increased similarly in glycolytic skeletal muscle from wild-type and TBC1D4-deficient mice. In contrast, 3 h after contraction or 6 h after AICAR stimulation, enhanced insulin-stimulated glucose uptake was evident in muscle from wild-type mice only. The enhanced insulin sensitivity in muscle from wild-type mice was associated with improved insulin-stimulated phosphorylation of TBC1D4 (Thr649 and Ser711) but not of TBC1D1. These results provide genetic evidence linking signaling through TBC1D4 to enhanced muscle insulin sensitivity after activation of the cellular energy sensor AMPK.

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Section: Discussionmentioning

confidence: 65%

TBC1D4 Is Necessary for Enhancing Muscle Insulin Sensitivity in Response to AICAR and Contraction

et al. 2019

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“…Exactly how this may relay to the regulation of insulin action following exercise is still unclear. Rodent studies suggest that the localization of TBC1D4 and protection against dephosphorylation mediated by prior exercise might be of importance (Zheng & Cartee, 2016;Arias et al 2018). In the present study, we showed decreased AMPKγ 3 expression in skeletal muscle in response to 12 weeks of cycling exercise, confirming previous observations (Frøsig et al 2004;Wojtaszewski et al 2005;Mortensen et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Exercise training reduces the insulin‐sensitizing effect of a single bout of exercise in human skeletal muscle

Steenberg

Jørgensen

Birk

et al. 2018

The Journal of Physiology

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Key points A single bout of exercise is capable of increasing insulin sensitivity in human skeletal muscle. Whether this ability is affected by training status is not clear. Studies in mice suggest that the AMPK‐TBC1D4 signalling axis is important for the increased insulin‐stimulated glucose uptake after a single bout of exercise. The present study is the first longitudinal intervention study to show that, although exercise training increases insulin‐stimulated glucose uptake in skeletal muscle at rest, it diminishes the ability of a single bout of exercise to enhance muscle insulin‐stimulated glucose uptake. The present study provides novel data indicating that AMPK in human skeletal muscle is important for the insulin‐sensitizing effect of a single bout of exercise. Abstract Not only chronic exercise training, but also a single bout of exercise, increases insulin‐stimulated glucose uptake in skeletal muscle. However, it is not well described how adaptations to exercise training affect the ability of a single bout of exercise to increase insulin sensitivity. Rodent studies suggest that the insulin‐sensitizing effect of a single bout of exercise is AMPK‐dependent (presumably via the α2β2γ3 AMPK complex). Whether this is also the case in humans is unknown. Previous studies have shown that exercise training decreases the expression of the α2β2γ3 AMPK complex and diminishes the activation of this complex during exercise. Thus, we hypothesized that exercise training diminishes the ability of a single bout of exercise to enhance muscle insulin sensitivity. We investigated nine healthy male subjects who performed one‐legged knee‐extensor exercise at the same relative intensity before and after 12 weeks of exercise training. Training increased V̇O2 peak and expression of mitochondrial proteins in muscle, whereas the expression of AMPKγ3 was decreased. Training also increased whole body and muscle insulin sensitivity. Interestingly, insulin‐stimulated glucose uptake in the acutely exercised leg was not enhanced further by training. Thus, the increase in insulin‐stimulated glucose uptake following a single bout of one‐legged exercise was lower in the trained vs. untrained state. This was associated with reduced signalling via confirmed α2β2γ3 AMPK downstream targets (ACC and TBC1D4). These results suggest that the insulin‐sensitizing effect of a single bout of exercise is also AMPK‐dependent in human skeletal muscle.

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“…Multiple lines of evidence support the idea that enhanced AS160 phosphorylation is linked to improved insulin sensitivity postexercise. Acute exercise can induce elevated Thr642 and/or Ser588 phosphorylation in the rat epitrochlearis muscle (3,10,17,48). Greater AS160 phosphorylation has also been reported in insulin-stimulated human muscle after exercise that improved insulin-stimulated glucose uptake (42).…”

Section: Introductionmentioning

confidence: 95%

Fiber type-selective exercise effects on AS160 phosphorylation

Wang

Arias

Oki

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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Earlier research using muscle tissue demonstrated that postexercise elevation in insulin-stimulated glucose uptake (ISGU) occurs concomitant with greater insulin-stimulated Akt substrate of 160 kDa (AS160) phosphorylation (pAS160) on sites that regulate ISGU. Because skeletal muscle is a heterogeneous tissue, we previously isolated myofibers from rat epitrochlearis to assess fiber type-selective ISGU. Exercise induced greater ISGU in type I, IIA, IIB, and IIBX but not IIX fibers. This study tested if exercise effects on pAS160 correspond with previously published fiber type-selective exercise effects on ISGU. Rats were studied immediately postexercise (IPEX) or 3.5 h postexercise (3.5hPEX) with time-matched sedentary controls. Myofibers dissected from the IPEX experiment were analyzed for fiber type (myosin heavy chain isoform expression) and key phosphoproteins. Isolated muscles from the 3.5hPEX experiment were incubated with or without insulin. Myofibers (3.5hPEX) were analyzed for fiber type, key phosphoproteins, and GLUT4 protein abundance. We hypothesized that insulin-stimulated pAS160 at 3.5hPEX would exceed sedentary controls only in fiber types characterized by greater ISGU postexercise. Values for phosphorylation of AMP-activated kinase substrates (acetyl CoA carboxylaseSer79 and AS160Ser704) from IPEX muscles exceeded sedentary values in each fiber type, suggesting exercise recruitment of all fiber types. Values for pAS160Thr642 and pAS160Ser704 from insulin-stimulated muscles 3.5hPEX exceeded sedentary values for type I, IIA, IIB, and IIBX but not IIX fibers. GLUT4 abundance was unaltered 3.5hPEX in any fiber type. These results advanced understanding of exercise-induced insulin sensitization by providing compelling support for the hypothesis that enhanced insulin-stimulated phosphorylation of AS160 is linked to elevated ISGU postexercise at a fiber type-specific level independent of altered GLUT4 expression.

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Akt Substrate of 160 kDa Dephosphorylation Rate Is Reduced in Insulin-Stimulated Rat Skeletal Muscle After Acute Exercise

Cited by 9 publications

References 11 publications

TBC1D4 Is Necessary for Enhancing Muscle Insulin Sensitivity in Response to AICAR and Contraction

TBC1D4 Is Necessary for Enhancing Muscle Insulin Sensitivity in Response to AICAR and Contraction

Exercise training reduces the insulin‐sensitizing effect of a single bout of exercise in human skeletal muscle

Fiber type-selective exercise effects on AS160 phosphorylation

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