title: Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice.
abstract: OBJECTIVE
  The NAD(+)-dependent protein deacetylase sirtuin (SIRT)1 is thought to be a key regulator of skeletal muscle metabolism. However, its precise role in the regulation of insulin sensitivity is unclear. Accordingly, we sought to determine the effect of skeletal muscle-specific overexpression of SIRT1 on skeletal muscle insulin sensitivity and whole-body energy metabolism.
  
  
  METHODS
  At 10 weeks of age, mice with muscle-specific overexpression of SIRT1 and their wild-type littermates were fed a standard diet with free access to chow or an energy-restricted (60% of standard) diet for 20 days. Energy expenditure and body composition were measured by indirect calorimetry and magnetic resonance imaging, respectively. Skeletal muscle insulin-stimulated glucose uptake was measured ex vivo in soleus and extensor digitorum longus muscles using a 2-deoxyglucose uptake technique with a physiological insulin concentration of 360 pmol/l (60 μU/ml).
  
  
  RESULTS
  Sirt1 mRNA and SIRT1 protein levels were increased by approximately 100- and 150-fold, respectively, in skeletal muscle of mice with SIRT1 overexpression compared with wild-type mice. Despite this large-scale overexpression of SIRT1, body composition, whole-body energy expenditure, substrate oxidation and voluntary activity were comparable between genotypes. Similarly, skeletal muscle basal and insulin-stimulated glucose uptake were unaltered with SIRT1 overexpression. Finally, while 20 days of energy restriction enhanced insulin-stimulated glucose uptake in skeletal muscles of wild-type mice, no additional effect of SIRT1 overexpression was observed.
  
  
  CONCLUSIONS
  These results demonstrate that upregulation of SIRT1 activity in skeletal muscle does not affect whole-body energy expenditure or enhance skeletal muscle insulin sensitivity in young mice on a standard diet with free access to chow or in young mice on energy-restricted diets.
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, 9500 Gilman Drive MC0863, La Jolla, CA 92093-0863, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: White
authors.forename: C E
authors.initials: CE
authors.lastname: McCurdy
authors.forename: A
authors.initials: A
authors.lastname: Philp
authors.forename: D L
authors.initials: DL
authors.lastname: Hamilton
authors.forename: C D
authors.initials: CD
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Schenk
mesh_terms: D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism / Q000502:physiology*; D005838:Genotype; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C470545:Sirt1 protein, mouse; D056564:Sirtuin 1