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

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.

• Authors: Maitea Guridi, Lionel A Tintignac, Shuo Lin, Barbara Kupr, Perrine Castets, Markus A Rüegg
• Journal: Science signaling (Sci Signal) Vol. 8 Issue 402 Pg. ra113 (Nov 10 2015) ISSN: 1937-9145 [Electronic] United States
• PMID: 26554817 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Fatty Acids
• Multiprotein Complexes
• Phenylbutyrates
• Tsc1 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins
• fibroblast growth factor 21
• Fibroblast Growth Factors
• 4-phenylbutyric acid
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Glucose

Topics

• Animals
• Endoplasmic Reticulum Stress
• Fatty Acids (metabolism)
• Female
• Fibroblast Growth Factors (antagonists & inhibitors, metabolism)
• Glucose (metabolism)
• Insulin Resistance
• Lipodystrophy (etiology, metabolism)
• Male
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Knockout
• Multiprotein Complexes (metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Oxidation-Reduction
• Phenotype
• Phenylbutyrates (pharmacology)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins (deficiency, genetics)