Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, 9500 Gilman Drive MC0863, La Jolla, CA 92093-0863, USA.
Diabetologia. 2013 Jul;56(7):1629-37. doi: 10.1007/s00125-013-2912-2. Epub 2013 Apr 19.
AIMS/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.
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).
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.
目的/假设：NAD(+)依赖性蛋白去乙酰化酶 SIRT1（Sirtuin1）被认为是骨骼肌代谢的关键调节因子。然而，其在胰岛素敏感性调节中的精确作用尚不清楚。因此，我们试图确定骨骼肌特异性过表达 SIRT1 对骨骼肌胰岛素敏感性和全身能量代谢的影响。
在 10 周龄时，肌肉特异性过表达 SIRT1 的小鼠及其野生型同窝仔鼠分别给予标准饮食（自由获取饲料）或能量限制（标准饮食的 60%）饮食 20 天。通过间接测热法和磁共振成像分别测量能量消耗和身体成分。使用 2-脱氧葡萄糖摄取技术，在生理胰岛素浓度 360pmol/l（60μU/ml）下，测量比目鱼肌和伸趾长肌的骨骼肌胰岛素刺激葡萄糖摄取。
与野生型小鼠相比，SIRT1 过表达小鼠的 Sirt1 mRNA 和 SIRT1 蛋白水平分别增加了约 100-和 150 倍。尽管 SIRT1 过表达幅度很大，但两种基因型的身体成分、全身能量消耗、底物氧化和自愿活动无差异。同样，SIRT1 过表达对骨骼肌基础和胰岛素刺激的葡萄糖摄取没有影响。最后，尽管 20 天的能量限制增强了野生型小鼠骨骼肌的胰岛素刺激葡萄糖摄取，但 SIRT1 过表达没有观察到额外的作用。
结论/解释：这些结果表明，在标准饮食（自由获取饲料）或能量限制饮食的年轻小鼠中，上调骨骼肌 SIRT1 活性不会影响全身能量消耗或增强骨骼肌胰岛素敏感性。
