Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle.
Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle.
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DOI：
10.1016/j.bbrc.2017.12.081
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发表时间：
2018-01-08
影响因子：
3.1
通讯作者：
Maegawa, Hiroshi
中科院分区：
文献类型：
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作者：
Murata, Koichiro;Morino, Katsutaro;Maegawa, Hiroshi
O-GlcNAc酰化是一种翻译后修饰，其特征在于通过O-GlcNAc转移酶（Ogt）将N-乙酰葡糖胺（GlcNAc）添加到蛋白质中。O-GlcNAc化的程度被认为与葡萄糖毒性和糖尿病并发症有关，因为GlcNAc是由糖酵解途径的分支产生的。然而，其在骨骼肌中的作用尚未完全阐明。在这项研究中，我们建立了骨骼肌特异性Ogt基因敲除（Ogt-MKO）小鼠，并分析了它们的葡萄糖代谢。在腹膜内葡萄糖耐量试验期间，Ogt-MKO小鼠的血糖略低于对照Ogt-flox小鼠。高脂饮食诱导的肥胖和胰岛素抵抗在Ogt-MKO小鼠中逆转。此外，12个月大的Ogt-MKO小鼠的脂肪和体重较低。单次运动显著降低了Ogt-MKO小鼠的血糖，这可能是因为较高的AMP活化蛋白激酶α（AMPK α）蛋白表达。此外，腹膜内注射AMPK激活剂5-氨基咪唑-4-甲酰胺核糖核苷酸导致Ogt-MKO小鼠的血糖水平比对照组更显著降低。最后，在C2 C12肌管中通过siRNA敲低Ogt显著增加AMPK α的蛋白表达、葡萄糖摄取和氧化。总之，O-GlcNAc酰化的丧失可能通过AMPK活化促进骨骼肌中的葡萄糖利用。骨骼肌中O-GlcNAc化的抑制可能通过增强运动期间的葡萄糖利用而具有抗糖尿病作用。
O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine (GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated. In this study, we created skeletal muscle-specific Ogt knockout (Ogt-MKO) mice and analyzed their glucose metabolism. During an intraperitoneal glucose tolerance test, blood glucose was slightly lower in Ogt-MKO mice than in control Ogt-flox mice. High fat diet-induced obesity and insulin resistance were reversed in Ogt-MKO mice. In addition, 12-month-old Ogt-MKO mice had lower adipose and body mass. A single bout of exercise significantly reduced blood glucose in Ogt-MKO mice, probably because of higher AMP-activated protein kinase alpha (AMPKalpha) protein expression. Furthermore, intraperitoneal injection of 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, resulted in a more marked decrease in blood glucose levels in Ogt-MKO mice than in controls. Finally, Ogt knockdown by siRNA in C2C12 myotubes significantly increased protein expression of AMPKalpha, glucose uptake and oxidation. In conclusion, loss of O-GlcNAcylation facilitates glucose utilization in skeletal muscle, potentially through AMPK activation. The inhibition of O-GlcNAcylation in skeletal muscle may have an anti-diabetic effect, through an enhancement of glucose utilization during exercise.