title: Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism.
abstract: BACKGROUND
  The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism.
  
  
  RESULTS
  We characterized the metabolic phenotype of young and old raptor muscle knock-out (RAmKO) and TSC1 muscle knock-out (TSCmKO) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated, respectively. Ten-week-old RAmKO mice are lean and insulin resistant with increased energy expenditure, and they are resistant to a high-fat diet (HFD). This correlates with an increased expression of histone deacetylases (HDACs) and a downregulation of genes involved in glucose and fatty acid metabolism. Ten-week-old TSCmKO mice are also lean, glucose intolerant with a decreased activation of protein kinase B (Akt/PKB) targets that regulate glucose transporters in the muscle. The mice are resistant to a HFD and show reduced accumulation of glycogen and lipids in the liver. Both mouse models suffer from a myopathy with age, with reduced fat and lean mass, and both RAmKO and TSCmKO mice develop insulin resistance and increased intramyocellular lipid content.
  
  
  CONCLUSIONS
  Our study shows that alterations of mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism. While both inhibition and constitutive activation of mTORC1 induce leanness and resistance to obesity, changes in the metabolism of muscle and peripheral organs are distinct. These results indicate that a balanced mTORC1 signaling in the muscle is required for proper metabolic homeostasis.
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Maitea
authors.initials: M
authors.lastname: Guridi
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kupr
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Klaas
authors.initials: K
authors.lastname: Romanino
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Falcetta
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland ; Present address: Neuromuscular Research Center, Departments of Neurology and Biomedicine, Pharmazentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Tintignac
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005838:Genotype; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology*; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013851:Thinness / Q000201:enzymology / Q000235:genetics; D013997:Time Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases
keywords: Diabetes; Metabolism; Muscle; Myopathy; Raptor; TSC1; mTOR