Role of Grb10 in mTORC1-dependent regulation of insulin signaling and action in human skeletal muscle cells

Role of Grb10 in mTORC1-dependent regulation of insulin signaling and action in human skeletal... Growth factor receptor-bound 10 (Grb10) is an adaptor protein that binds to the insulin receptor, upon which insulin signaling and action is thought to be inhibited. Grb10 is also a substrate for the mechanistic target of rapamycin complex 1 (mTORC1) that mediates its feedback inhibition on phosphatidylinositide 3-kinase (PI3K)/Akt signaling. To characterize the function of Grb10 and its regulation by mTORC1 in human muscle, primary skeletal muscle cells were isolated from healthy lean young men and then induced to differentiate into myotubes. Knockdown of Grb10 enhanced insulin-induced PI3K/Akt signaling and glucose uptake in myotubes, reinforcing the notion underlying its function as a negative regulator of insulin action in human muscle. The increased insulin sensitivity responsiveness in Grb10-silenced myotubes was associated with higher abundance of the insulin receptor. Furthermore, insulin and amino acids independently and additively stimulated phosphorylation of Grb10 at Ser476. However, acute inhibition of mTORC1 with rapamycin blocked Grb10 Ser476 phosphorylation and repressed a negative-feedback loop on PI3K/Akt signaling that increased myotube responsiveness to insulin. Chronic rapamycin treatment reduced Grb10 protein abundance in conjunction with increased insulin receptor protein levels. Based on these findings, we propose that mTORC1 controls PI3K/Akt signaling through modulation of insulin receptor abundance by Grb10. These findings have potential implications for obesity-linked insulin resistance, as well as clinical use of mTORC1 inhibitors. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Endocrinology and Metabolism The American Physiological Society

Role of Grb10 in mTORC1-dependent regulation of insulin signaling and action in human skeletal muscle cells

Role of Grb10 in mTORC1-dependent regulation of insulin signaling and action in human skeletal muscle cells

1 RUNINING HEAD: Grb10 mediates mTORC1 feedback on insulin signaling 5 Role of Grb10 in mTORC1-dependent Regulation of Insulin Signaling and 6 Action in Human Skeletal Muscle Cells 1 1 1-3 8 Ashlin M. Edick , Olivia Auclair , and Sergio A. Burgos 10 Department of Animal Science, McGill University 11 Department of Medicine, McGill University 12 Metabolic Disorders and Complications Program, Research Institute of McGill University Health 13 Centre 15 Corresponding author: 16 Sergio A. Burgos 17 Department of Animal Science 18 Faculty of Agricultural and Environmental Sciences 19 McGill University 20 21,111 Lakeshore Road 21 Sainte-Anne-de-Bellevue, QC, H9X 3V9, Canada 22 sergio.burgos@mcgill.ca 23 Telephone: (514) 398-7802 24 Fax: (514) 398-7990 25 ABSTRACT 26 Growth factor receptor-bound 10 (Grb10) is an adaptor protein that binds to the insulin receptor, 27 upon which insulin signaling and action is thought to be inhibited. Grb10 is also a substrate for the 28 mechanistic target of rapamycin complex 1 (mTORC1) that mediates its feedback inhibition on 29 phosphatidylinositide 3-kinase (PI3K)/Akt signaling. To characterize the function of Grb10 and 30 its regulation by mTORC1 in human muscle, primary skeletal muscle cells were isolated from 31 healthy lean young men and then induced to differentiate into myotubes. Knockdown of Grb10 32 enhanced insulin-induced PI3K/Akt signaling and glucose uptake in myotubes, reinforcing the 33 notion underlying its function as a negative regulator of insulin action in human muscle. The 34 increased insulin sensitivity responsiveness in Grb10-silenced myotubes was associated with 35 higher abundance of the insulin receptor. Furthermore, insulin and amino acids independently and 36 additively stimulated phosphorylation of Grb10 at Ser476. However, acute inhibition of mTORC1 37 with rapamycin blocked Grb10 Ser476 phosphorylation and repressed a negative-feedback loop 38 on PI3K/Akt signaling that increased myotube responsiveness...
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ISSN
0193-1849
eISSN
1522-1555
DOI
10.1152/ajpendo.00025.2019
Publisher site
See Article on Publisher Site

Abstract

Growth factor receptor-bound 10 (Grb10) is an adaptor protein that binds to the insulin receptor, upon which insulin signaling and action is thought to be inhibited. Grb10 is also a substrate for the mechanistic target of rapamycin complex 1 (mTORC1) that mediates its feedback inhibition on phosphatidylinositide 3-kinase (PI3K)/Akt signaling. To characterize the function of Grb10 and its regulation by mTORC1 in human muscle, primary skeletal muscle cells were isolated from healthy lean young men and then induced to differentiate into myotubes. Knockdown of Grb10 enhanced insulin-induced PI3K/Akt signaling and glucose uptake in myotubes, reinforcing the notion underlying its function as a negative regulator of insulin action in human muscle. The increased insulin sensitivity responsiveness in Grb10-silenced myotubes was associated with higher abundance of the insulin receptor. Furthermore, insulin and amino acids independently and additively stimulated phosphorylation of Grb10 at Ser476. However, acute inhibition of mTORC1 with rapamycin blocked Grb10 Ser476 phosphorylation and repressed a negative-feedback loop on PI3K/Akt signaling that increased myotube responsiveness to insulin. Chronic rapamycin treatment reduced Grb10 protein abundance in conjunction with increased insulin receptor protein levels. Based on these findings, we propose that mTORC1 controls PI3K/Akt signaling through modulation of insulin receptor abundance by Grb10. These findings have potential implications for obesity-linked insulin resistance, as well as clinical use of mTORC1 inhibitors.

Journal

AJP - Endocrinology and MetabolismThe American Physiological Society

Published: Jan 22, 2019

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