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Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice
journal contribution
posted on 2013-07-01, 00:00 authored by A T White, C E McCurdy, A Philp, Lee HamiltonLee Hamilton, C D Johnson, S SchenkAIMS/HYPOTHESIS: 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/INTERPRETATION: 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.
History
Journal
DiabetologiaVolume
56Issue
7Pagination
1629 - 1637Publisher
SpringerLocation
Berlin, GermanyPublisher DOI
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eISSN
1432-0428Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2013, Springer-Verlag Berlin HeidelbergUsage metrics
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AnimalsBody CompositionElectrophoresis, Polyacrylamide GelEnergy MetabolismGenotypeInsulin ResistanceMiceMuscle, SkeletalReverse Transcriptase Polymerase Chain ReactionSirtuin 1Science & TechnologyLife Sciences & BiomedicineEndocrinology & Metabolism2-Deoxyglucose uptakeEnergy restrictionInsulin sensitivitySIRT1Skeletal muscleACTIVATED PROTEIN-KINASECALORIE RESTRICTIONGLUCOSE-UPTAKEFAT OXIDATIONMETABOLISMDIETAMPKDEACETYLASEEXERCISEPGC-1-ALPHA
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