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Skeletal muscle mTORC1 regulates whole-body metabolism

Ormazabal, Maitea Guridi. Skeletal muscle mTORC1 regulates whole-body metabolism. 2015, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11666

Abstract

Skeletal muscle, which represents over 40% of the total body mass, is a dynamic tissue with a key role in the maintenance of metabolic homeostasis. Several lines of evidence indicate that alterations of the normal muscle function, as for example in muscular dystrophies, obesity or diabetes, can affect the metabolism at the whole-body level (DeFronzo & Tripathy, 2009; Llagostera et al, 2007). We focused on the mTORC1 signaling pathway in skeletal muscle, responsible for the transduction of insulin signaling and nutrient sensing from the cell surface to the increased protein synthesis and anabolic processes that allow cells to grow and proliferate (Laplante & Sabatini, 2012). We decided to characterize the metabolic phenotype of young and old RAmKO (Raptor muscle knock-out) and TSCmKO (TSC1 muscle knock-out) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated respectively. Young RAmKO mice were lean and dystrophic, insulin resistant, with increased energy expenditure and resistant to a HFD. This correlated with an increase in histone deacetylases (HDACs) and a down-regulation of genes involved in glucose and fatty acid metabolism. Young TSCmKO mice were lean, glucose intolerant with a decrease in Akt signaling pathway, resistant to a HFD and showed reduced accumulation of glycogen and lipids in the liver. Both mouse models developed a myopathy with age, with decreased fat and lean mass, and both RAmKO and TSCmKO mice developed metabolic acidosis with insulin resistance and increased intramyocelular lipid content.
While the effects of mTORC1 inhibition in skeletal muscle of young mice were limited to muscle, its sustained activation caused changes not only in skeletal muscle but also at the whole-body level. TSCmKO mice were lean, with increased insulin sensitivity and fatty acid oxidation, and showed changes in other metabolic organs. This indicated the possible influence of a muscle secreted myokine. Secretion of fibroblast growth factor 21 (FGF21) by skeletal muscle has been shown to protect from diet-induced obesity and insulin resistance (Kim et al, 2013c). We showed that most of the metabolic phenotype of TSCmKO mice was due to increased plasma concentrations of FGF21, a hormone that stimulates glucose uptake and fatty acid oxidation. FGF21 was released from skeletal muscle mainly because of mTORC1-triggered ER stress and activation of the PERK-eIF2α-ATF4 pathway. Treatment of TSCmKO mice with a chemical chaperone, which 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. We further confirmed the involvement of muscle FGF21 in the development of the TSCmKO mice phenotype by genetic knock-out of FGF21 specifically in skeletal muscle. DKO mice (muscle TSC1/FGF21 KO) showed normalized plasma glucose and ketone body levels, as well as an increase in body weight, growth and lean mass. This was a direct consequence of muscle secreted FGF21, as plasma FGF21 levels were normalized in DKO mice. Surprisingly, fat mass was still reduced in these mice. We observed increased expression of fatty acid oxidation markers in the muscle of DKO and a decrease in the lipid content, which could contribute to the ongoing wasting of the adipose tissue. Nevertheless, this could indicate either a compensatory mechanism that did not allow DKO mice to gain fat mass, or a FGF21-independent mechanism causing the increased lipolysis of white adipose tissue. Interestingly, when we knocked-out FGF21 specifically in skeletal muscle in a non-genetically altered mouse, we observed the development of obesity induced diabetes, as these mice became heavier, with increased fat mass, higher plasma glucose levels and glucose intolerance.
In conclusion, we have confirmed that alterations to mTORC1 signaling pathway in skeletal muscle directly affect whole body metabolism, which highlights the importance of this tissue in maintaining energy stability. Moreover, we show that proper balance in mTORC1 signaling is essential for muscle tissue integrity and metabolic homeostasis, since both long-term activation and inhibition originated a myopathy that mimicked the main metabolic complications of dystrophic patients. Furthermore, activation of mTORC1 in skeletal muscle, through induction of ER stress, increased the secretion of FGF21 into the circulation, which caused progressive metabolic adaptations to compensate for the altered muscle dynamics. Thus, muscle mTORC1 could serve as a potential target to treat metabolic complications of diseases like diabetes, obesity and muscle dystrophies.
Advisors:Rüegg, Markus A. and Handschin, Christoph
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
Item Type:Thesis
Thesis no:11666
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (217 Seiten)
Language:English
Identification Number:
Last Modified:22 Aug 2016 12:41
Deposited On:19 Aug 2016 09:16

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