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

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 regulatio...

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Autores principales: Liu, Xin‐Hua, Bauman, William A., Cardozo, Christopher P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121119/
https://www.ncbi.nlm.nih.gov/pubmed/30252210
http://dx.doi.org/10.14814/phy2.13837
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author Liu, Xin‐Hua
Bauman, William A.
Cardozo, Christopher P.
author_facet Liu, Xin‐Hua
Bauman, William A.
Cardozo, Christopher P.
author_sort Liu, Xin‐Hua
collection PubMed
description 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 GSK3β 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.
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spelling pubmed-61211192018-09-05 Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts Liu, Xin‐Hua Bauman, William A. Cardozo, Christopher P. Physiol Rep Original Research 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 GSK3β 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. John Wiley and Sons Inc. 2018-09-03 /pmc/articles/PMC6121119/ /pubmed/30252210 http://dx.doi.org/10.14814/phy2.13837 Text en © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Liu, Xin‐Hua
Bauman, William A.
Cardozo, Christopher P.
Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
title Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
title_full Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
title_fullStr Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
title_full_unstemmed Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
title_short Myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
title_sort myostatin inhibits glucose uptake via suppression of insulin‐dependent and ‐independent signaling pathways in myoblasts
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121119/
https://www.ncbi.nlm.nih.gov/pubmed/30252210
http://dx.doi.org/10.14814/phy2.13837
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