UC San Diego

Exercise (i.e. contraction) robustly stimulates skeletal muscle glucose uptake, making it a cornerstone non-pharmaceutical intervention for treating clinical hyperglycemia and insulin-resistance. Remarkably, however, the molecular steps that regulate contraction-stimulated glucose uptake by skeletal muscle remain incompletely defined. The mammalian ortholog of Sir2, sirtuin 1 (SIRT1), is a protein deacetylase that is thought to link perturbations in energy flux associated with exercise, particularly at the level of NAD+ and NAD+/NADH, to subsequent cellular adaptations. Nevertheless, its role in contraction-stimulated glucose uptake has not been defined. The objective of this study was to determine the contribution of SIRT1 to contraction-stimulated glucose uptake in mouse skeletal muscle. Using radioactive 2-deoxyglucose uptake (2DOGU) approach, we measured ex vivo glucose uptake in unstimulated and electrically-stimulated (100 Hz contraction [2s train, 0.2ms pulse, 35V] every 15s for 10 min) extensor digitorum longus (EDL) and soleus from ~15 week old male and female mice with muscle-specific knockout of SIRT1 (mKO) and their wildtype (WT) littermates. As expected, force output decreased over the contraction protocol, although there were no differences in the rate of fatigue between genotypes. In EDL and soleus from WT mice, 2DOGU was ~2.5-fold higher in contracted vs. rested muscle, regardless of sex, and this effect was not impaired in mKO mice. Interestingly, the absolute rate of contraction-stimulated 2DOGU was ~1.3-fold higher in both the soleus and EDL of female compared to male mice, regardless of genotype. Taken together, our findings demonstrate that SIRT1 is not required for contraction-stimulated glucose uptake in mouse skeletal muscle.