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Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts.

ABSTRACT: The glucose transporter 4 (Glut4) mediates insulin-dependent glucose uptake. Glut4 expression levels are correlated with whole-body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface. Expression of Glut4 is subject to tissue-specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated. Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn levels in muscle are associated with obesity and type-2 diabetes in both human and mouse models, Mstn null mice exhibit immunity to dietary-induced obesity and insulin resistance. The molecular mechanisms by which Mstn initiates the development of insulin resistance and disorders of glucose disposal are not well delineated. Here we investigated effects of Mstn on insulin action in C2C12 cells. Mstn significantly reduced basal and insulin-induced IRS-1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3? phosphorylation at Ser9. In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin-induced Glut4 membrane translocation and glucose uptake. Conversely, SB431542, a Smad2/3 inhibitor, significantly increased cellular response to insulin. Mstn decreased AMP-activated protein kinase (AMPK) activity accompanied by reduced Glut4 gene expression and glucose uptake, which were partially reversed by AICAR, an AMPK activator. These data suggest that Mstn inhibits Glut4 expression and insulin-induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin-desensitizing effect and indirect suppression of AMPK activation.

SUBMITTER: Liu XH

PROVIDER: S-EPMC6121119 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts.

Liu Xin-Hua XH Bauman William A WA Cardozo Christopher P CP

Physiological reports 20180901 17

The glucose transporter 4 (Glut4) mediates insulin-dependent glucose uptake. Glut4 expression levels are correlated with whole-body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface. Expression of Glut4 is subject to tissue-specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated. Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn ...[more]

PMID: 30252210

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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

Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts.

Publications

Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts.

Similar Datasets

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