Research ArticlesMUSCLE BIOLOGY

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

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Science Signaling  10 Nov 2015:
Vol. 8, Issue 402, pp. ra113
DOI: 10.1126/scisignal.aab3715

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Thinner with FGF21

Skeletal muscle alters whole-body metabolism through the release of hormones into the bloodstream called myokines. Guridi et al. found that skeletal muscle released a hormone called FGF21 in mice with skeletal muscle–specific activation of mTORC1, a protein complex that links nutrient availability to cell growth. Compared to control mice, these mice weighed less, likely because of increased fatty acid oxidation and increased energy expenditure, and had lower plasma concentrations of glucose and insulin. Systemic administration of antibodies directed against FGF21 reversed these metabolic changes. Thus, FGF21 released from skeletal muscle can mediate changes in whole-body metabolism.


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.

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