Brandon Amanda E, Tid-Ang Jennifer, Wright Lauren E, Stuart Ella, Suryana Eurwin, Bentley Nicholas, Turner Nigel, Cooney Gregory J, Ruderman Neil B, Kraegen Edward W
Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW, 2010, Australia.
UNSW Medicine, University of New South Wales, Sydney, Australia.
PLoS One. 2015 Mar 23;10(3):e0121959. doi: 10.1371/journal.pone.0121959. eCollection 2015.
SIRT1 is a NAD+-dependent deacetylase thought to regulate cellular metabolic pathways in response to alterations in nutrient flux. In the current study we investigated whether acute changes in SIRT1 expression affect markers of muscle mitochondrial content and also determined whether SIRT1 influenced muscle insulin resistance induced by acute glucose oversupply. In male Wistar rats either SIRT1 or a deacetylase inactive mutant form (H363Y) was electroprated into the tibialis cranialis (TC) muscle. The other leg was electroporated with an empty control vector. One week later, glucose was infused and hyperglycaemia was maintained at ~11mM. After 5 hours, 11mM glucose induced significant insulin resistance in skeletal muscle. Interestingly, overexpression of either SIRT1 or SIRT1 (H363Y) for 1 week did not change markers of mitochondrial content or function. SIRT1 or SIRT1 (H363Y) overexpression had no effect on the reduction in glucose uptake and glycogen synthesis in muscle in response to hyperglycemia. Therefore we conclude that acute increases in SIRT1 protein have little impact on mitochondrial content and that overexpressing SIRT1 does not prevent the development of insulin resistance during hyperglycaemia.
SIRT1是一种依赖烟酰胺腺嘌呤二核苷酸（NAD+）的去乙酰化酶，被认为可响应营养物质通量的变化来调节细胞代谢途径。在本研究中，我们调查了SIRT1表达的急性变化是否会影响肌肉线粒体含量标志物，还确定了SIRT1是否会影响由急性葡萄糖供应过多诱导的肌肉胰岛素抵抗。在雄性Wistar大鼠中，将SIRT1或一种去乙酰化酶无活性突变体形式（H363Y）电穿孔导入颅侧胫骨肌（TC）。另一条腿用电穿孔空对照载体处理。一周后，输注葡萄糖并将高血糖维持在约11mM。5小时后，11mM葡萄糖在骨骼肌中诱导出显著的胰岛素抵抗。有趣的是，SIRT1或SIRT1（H363Y）过表达1周并未改变线粒体含量或功能标志物。SIRT1或SIRT1（H363Y）过表达对高血糖状态下肌肉葡萄糖摄取和糖原合成的降低没有影响。因此，我们得出结论，SIRT1蛋白的急性增加对线粒体含量影响很小，并且过表达SIRT1并不能预防高血糖期间胰岛素抵抗的发展。
