Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase with a large range of target proteins thought to be important for many cellular processes including mitochondrial function and metabolism. Because of the importance of skeletal muscle in the postprandial disposal of glucose, we investigated the impact of SIRT1 deletion in muscle under conditions where SIRT1 activity is normally increased (fasting) or decreased (fed and/or high fat diet (HFD)).
Skeletal muscle specific SIRT1 knockout (mKO) mice were generated by mating floxed mice harbouring loxP sites flanking exon4 of the SIRT1 gene with mice expressing Cre recombinase under the control of the skeletal actin promoter. Floxed litter mates served as controls (WT). At ~25 weeks of age, male mice underwent glucose tolerance tests (2 g/kg) either on a chow or after 1 week HFD (45% fat). Some animals on a chow diet were euthanased in either the fed state or after 36h fasting.
Body weights were similar in the WT and mKO mice (33.4 ± 0.5g v 32.6 ± 0.6g). mKO mice showed no difference in glucose tolerance on a chow diet (iAUC WT 734±67 v mKO 836±68 mmol/l∙90min), and became equally intolerant after 1 week on a HFD (iAUC WT 1421±88 v mKO 1401±105 mmol/l∙90min). Muscle, liver and fat pad weights did not differ between WT and mKO mice, and decreased equally after fasting (p<0.05). Muscle glycogen levels decreased similarly after fasting in both groups (p<0.05). Immunoblotting showed similar levels of components of the mitochondrial respiratory chain in WT and mKO muscle.
The current study demonstrates that deletion of SIRT1 specifically in muscle of male mice does not alter body weight or composition, glucose tolerance or the response to fasting or HFD. These results suggest that SIRT1 activity is not essential for normal mitochondrial biogenesis and glucose metabolism in mouse skeletal muscle.