ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.

<h4>Background</h4>Anabolic resistance is the inability to increase protein synthesis in response to an increase in amino acids following a meal. One potential mediator of anabolic resistance is endoplasmic reticulum (ER) stress. The purpose of the present study was to test whether ER st...

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Autores principales:	Louise Deldicque, Luc Bertrand, Amy Patton, Marc Francaux, Keith Baar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df42a634e2b24edb93baa00d973584f0
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spelling	oai:doaj.org-article:df42a634e2b24edb93baa00d973584f02021-11-18T06:51:54ZER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.1932-620310.1371/journal.pone.0020993https://doaj.org/article/df42a634e2b24edb93baa00d973584f02011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21698202/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Anabolic resistance is the inability to increase protein synthesis in response to an increase in amino acids following a meal. One potential mediator of anabolic resistance is endoplasmic reticulum (ER) stress. The purpose of the present study was to test whether ER stress impairs the response to growth factors and leucine in muscle cells.<h4>Methods</h4>Muscle cells were incubated overnight with tunicamycin or thapsigargin to induce ER stress and the activation of the unfolded protein response, mTORC1 activity at baseline and following insulin and amino acids, as well as amino acid transport were determined.<h4>Results</h4>ER stress decreased basal phosphorylation of PKB and S6K1 in a dose-dependent manner. In spite of the decrease in basal PKB phosphorylation, insulin (10-50 nM) could still activate both PKB and S6K1. The leucine (2.5-5 mM)-induced phosphorylation of S6K1 on the other hand was repressed by low concentrations of both tunicamycin and thapsigargin. To determine the mechanism underlying this anabolic resistance, several inhibitors of mTORC1 activation were measured. Tunicamycin and thapsigargin did not change the phosphorylation or content of either AMPK or JNK, both increased TRB3 mRNA expression and thapsigargin increased REDD1 mRNA. Tunicamycin and thapsigargin both decreased the basal phosphorylation state of PRAS40. Neither tunicamycin nor thapsigargin prevented phosphorylation of PRAS40 by insulin. However, since PKB is not activated by amino acids, PRAS40 phosphorylation remained low following the addition of leucine. Blocking PKB using a specific inhibitor had the same effect on both PRAS40 and leucine-induced phosphorylation of S6K1.<h4>Conclusion</h4>ER stress induces anabolic resistance in muscle cells through a PKB/PRAS40-induced blockade of mTORC1.Louise DeldicqueLuc BertrandAmy PattonMarc FrancauxKeith BaarPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 6, p e20993 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Louise Deldicque Luc Bertrand Amy Patton Marc Francaux Keith Baar ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.
description	<h4>Background</h4>Anabolic resistance is the inability to increase protein synthesis in response to an increase in amino acids following a meal. One potential mediator of anabolic resistance is endoplasmic reticulum (ER) stress. The purpose of the present study was to test whether ER stress impairs the response to growth factors and leucine in muscle cells.<h4>Methods</h4>Muscle cells were incubated overnight with tunicamycin or thapsigargin to induce ER stress and the activation of the unfolded protein response, mTORC1 activity at baseline and following insulin and amino acids, as well as amino acid transport were determined.<h4>Results</h4>ER stress decreased basal phosphorylation of PKB and S6K1 in a dose-dependent manner. In spite of the decrease in basal PKB phosphorylation, insulin (10-50 nM) could still activate both PKB and S6K1. The leucine (2.5-5 mM)-induced phosphorylation of S6K1 on the other hand was repressed by low concentrations of both tunicamycin and thapsigargin. To determine the mechanism underlying this anabolic resistance, several inhibitors of mTORC1 activation were measured. Tunicamycin and thapsigargin did not change the phosphorylation or content of either AMPK or JNK, both increased TRB3 mRNA expression and thapsigargin increased REDD1 mRNA. Tunicamycin and thapsigargin both decreased the basal phosphorylation state of PRAS40. Neither tunicamycin nor thapsigargin prevented phosphorylation of PRAS40 by insulin. However, since PKB is not activated by amino acids, PRAS40 phosphorylation remained low following the addition of leucine. Blocking PKB using a specific inhibitor had the same effect on both PRAS40 and leucine-induced phosphorylation of S6K1.<h4>Conclusion</h4>ER stress induces anabolic resistance in muscle cells through a PKB/PRAS40-induced blockade of mTORC1.
format	article
author	Louise Deldicque Luc Bertrand Amy Patton Marc Francaux Keith Baar
author_facet	Louise Deldicque Luc Bertrand Amy Patton Marc Francaux Keith Baar
author_sort	Louise Deldicque
title	ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.
title_short	ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.
title_full	ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.
title_fullStr	ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.
title_full_unstemmed	ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.
title_sort	er stress induces anabolic resistance in muscle cells through pkb-induced blockade of mtorc1.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/df42a634e2b24edb93baa00d973584f0
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ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1.

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