Combined overexpression of SIRT1 and knockout of GCN5 in adult skeletal muscle does not affect glucose homeostasis or exercise performance in mice

Am J Physiol Endocrinol Metab. 2020 Feb 1;318(2):E145-E151. doi: 10.1152/ajpendo.00370.2019. Epub 2019 Dec 3.


Sirtuin 1 (SIRT1) and general control of amino acid synthesis 5 (GCN5) regulate mitochondrial biogenesis via opposing modulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) acetylation status and activity. However, the combined contribution of SIRT1 and GCN5 to skeletal muscle metabolism and endurance performance in vivo is unknown. In this study, we investigated the impact of combined skeletal muscle-specific overexpression of SIRT1 and deletion of GCN5 on glucose homeostasis, skeletal muscle mitochondrial biogenesis and function, and metabolic adaptation to endurance exercise training in mice. We generated mice with combined and tamoxifen-inducible skeletal muscle-specific overexpression of SIRT1 and knockout of GCN5 (dTG) and floxed [wild type (WT)] littermates using a Cre-LoxP approach. All mice were treated with tamoxifen at 5-6 wk of age, and 4-7 wk later glucose homeostasis, skeletal muscle contractile function, mitochondrial function, and the effects of 14 days of voluntary wheel running on expression of metabolic proteins and exercise capacity were assessed. There was no difference in oral glucose tolerance, skeletal muscle contractile function, mitochondrial abundance, or maximal respiratory capacity between dTG and WT mice. Additionally, there were no genotype differences in exercise performance and markers of mitochondrial biogenesis after 14 days of voluntary wheel running. These results demonstrate that combined overexpression of SIRT1 and loss of GCN5 in vivo does not promote metabolic remodeling in skeletal muscle of sedentary or exercise-trained mice.

Keywords: acetyltransferase; deacetylase; mitochondria; peroxisome proliferator-activated receptor-γ coactivator 1α.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaerobic Threshold / genetics
  • Animals
  • Glucose / metabolism*
  • Glucose Intolerance / genetics
  • Homeostasis / genetics*
  • Humans
  • Mice
  • Mice, Knockout
  • Mitochondria, Muscle / metabolism
  • Muscle Contraction / physiology
  • Muscle, Skeletal / metabolism*
  • Organelle Biogenesis
  • Physical Conditioning, Animal / physiology*
  • Running
  • Sirtuin 1 / biosynthesis*
  • Sirtuin 1 / genetics*
  • p300-CBP Transcription Factors / genetics*


  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Glucose