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Prior exercise in humans redistributes intramuscular GLUT4 and enhances insulin-stimulated sarcolemmal and endosomal GLUT4 translocation.

ABSTRACT: OBJECTIVE:Exercise is a cornerstone in the management of skeletal muscle insulin-resistance. A well-established benefit of a single bout of exercise is increased insulin sensitivity for hours post-exercise in the previously exercised musculature. Although rodent studies suggest that the insulin-sensitization phenomenon involves enhanced insulin-stimulated GLUT4 cell surface translocation and might involve intramuscular redistribution of GLUT4, the conservation to humans is unknown. METHODS:Healthy young males underwent an insulin-sensitizing one-legged kicking exercise bout for 1 h followed by fatigue bouts to exhaustion. Muscle biopsies were obtained 4 h post-exercise before and after a 2-hour hyperinsulinemic-euglycemic clamp. RESULTS:A detailed microscopy-based analysis of GLUT4 distribution within seven different myocellular compartments revealed that prior exercise increased GLUT4 localization in insulin-responsive storage vesicles and T-tubuli. Furthermore, insulin-stimulated GLUT4 localization was augmented at the sarcolemma and in the endosomal compartments. CONCLUSIONS:An intracellular redistribution of GLUT4 post-exercise is proposed as a molecular mechanism contributing to the insulin-sensitizing effect of prior exercise in human skeletal muscle.

SUBMITTER: Knudsen JR

PROVIDER: S-EPMC7240215 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Prior exercise in humans redistributes intramuscular GLUT4 and enhances insulin-stimulated sarcolemmal and endosomal GLUT4 translocation.

Knudsen Jonas R JR Steenberg Dorte E DE Hingst Janne R JR Hodgson Lorna R LR Henriquez-Olguin Carlos C Li Zhencheng Z Kiens Bente B Richter Erik A EA Wojtaszewski Jørgen F P JFP Verkade Paul P Jensen Thomas E TE

Molecular metabolism 20200417

<h4>Objective</h4>Exercise is a cornerstone in the management of skeletal muscle insulin-resistance. A well-established benefit of a single bout of exercise is increased insulin sensitivity for hours post-exercise in the previously exercised musculature. Although rodent studies suggest that the insulin-sensitization phenomenon involves enhanced insulin-stimulated GLUT4 cell surface translocation and might involve intramuscular redistribution of GLUT4, the conservation to humans is unknown.<h4>Me ...[more]

PMID: 32305516

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Project description:Impaired insulin-mediated glucose uptake characterizes cardiac muscle in humans and animals with insulin resistance and diabetes, despite preserved or enhanced phosphatidylinositol 3-kinase (PI3K) and the serine-threonine kinase, Akt-signaling, via mechanisms that are incompletely understood. One potential mechanism is PI3K- and Akt-mediated activation of mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K), which may impair insulin-mediated activation of insulin receptor substrate (IRS)1/2 via inhibitory serine phosphorylation or proteasomal degradation. To gain mechanistic insights by which constitutive activation of PI3K or Akt may desensitize insulin-mediated glucose uptake in cardiomyocytes, we examined mice with cardiomyocyte-restricted, constitutive or inducible overexpression of a constitutively activated PI3K or a myristoylated Akt1 (myrAkt1) transgene that also expressed a myc-epitope-tagged glucose transporter type 4 protein (GLUT4). Although short-term activation of PI3K and myrAkt1 increased mTOR and S6 signaling, there was no impairment in insulin-mediated activation of IRS1/2. However, insulin-mediated glucose uptake was reduced by 50-80%. Although longer-term activation of Akt reduced IRS2 protein content via an mTORC1-mediated mechanism, treatment of transgenic mice with rapamycin failed to restore insulin-mediated glucose uptake, despite restoring IRS2. Transgenic activation of Akt and insulin-stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin-stimulated wild-type controls. Despite preserved GLUT4 translocation, glucose uptake was not elevated by the presence of constitutive activation of PI3K and Akt. Hexokinase II activity was preserved in myrAkt1 hearts. Thus, constitutive activation of PI3K and Akt in cardiomyocytes impairs GLUT4-mediated glucose uptake via mechanisms that impair the function of GLUT4 after its plasma-membrane insertion.

Dataset Information

Prior exercise in humans redistributes intramuscular GLUT4 and enhances insulin-stimulated sarcolemmal and endosomal GLUT4 translocation.

Publications

Prior exercise in humans redistributes intramuscular GLUT4 and enhances insulin-stimulated sarcolemmal and endosomal GLUT4 translocation.

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