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Activation of mTORC1 in skeletal muscle regulates whole-body metabolism through FGF21

Guridi, Maitea and Tintignac, Lionel A. and Lin, Shuo and Kupr, Barbara and Castets, Perrine and Rüegg, Markus A.. (2015) Activation of mTORC1 in skeletal muscle regulates whole-body metabolism through FGF21. Science Signaling, 8 (402). ra113.

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Abstract

Skeletal muscle is the largest organ, comprising 40% of the total body lean mass, and affects whole-body metabolism in multiple ways. We investigated the signaling pathways involved in this process using TSCmKO mice, which have a skeletal muscle-specific depletion of TSC1 (tuberous sclerosis complex 1). This deficiency results in the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1), which enhances cell growth by promoting protein synthesis. TSCmKO mice were lean, with increased insulin sensitivity, as well as changes in white and brown adipose tissue and liver indicative of increased fatty acid oxidation. These differences were due to increased plasma concentrations of fibroblast growth factor 21 (FGF21), a hormone that stimulates glucose uptake and fatty acid oxidation. The skeletal muscle of TSCmKO mice released FGF21 because of mTORC1-triggered endoplasmic reticulum (ER) stress and activation of a pathway involving PERK (protein kinase RNA-like ER kinase), eIF2α (eukaryotic translation initiation factor 2α), and ATF4 (activating transcription factor 4). Treatment of TSCmKO mice with a chemical chaperone that alleviates ER stress reduced FGF21 production in muscle and increased body weight. Moreover, injection of function-blocking antibodies directed against FGF21 largely normalized the metabolic phenotype of the mice. Thus, sustained activation of mTORC1 signaling in skeletal muscle regulated whole-body metabolism through the induction of FGF21, which, over the long term, caused severe lipodystrophy.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for the Advancement of Science
ISSN:1945-0877
e-ISSN:1937-9145
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:19 Mar 2019 08:16
Deposited On:25 May 2016 06:37

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