A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice
A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice
复制标题
Tbc1d1 Ser231Ala 敲入突变会部分损害 AICAR，但不会损害小鼠运动诱导的肌肉葡萄糖摄取。
DOI：
10.1007/s00125-016-4151-9
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发表时间：
2017-02-01
期刊：
影响因子：
8.2
通讯作者：
Wang, Hong Yu
中科院分区：
文献类型：
--
作者：
Chen, Qiaoli;Xie, Bingxian;Wang, Hong Yu
TBC 1D 1（tre-2/USP 6，BUB 2，cdc 16 domain family member 1）是一种Rab GTP酶激活蛋白（RabGAP），参与调节GLUT 4转运。TBC 1D 1可以被Ser（231）上的AMP活化蛋白激酶（AMPK）磷酸化，从而与14-3-3蛋白相互作用。鉴于AMPK在调节胰岛素非依赖性肌肉葡萄糖摄取中的关键作用，我们假设TBC 1D 1-Ser（231）磷酸化和/或14-3-3结合可能介导AMPK调控的葡萄糖稳态。（Ser 231 Ala）-敲入突变或携带骨骼肌特异性Ampk α 1/α 2（也称为Prkaa 1/2）响应AMPK激活剂5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）的双敲除突变。在Tbc 1d 1（Ser 231 Ala）-敲入小鼠中测定了运动诱导的肌肉葡萄糖摄取和运动能力。结果小鼠骨骼肌特异性Ampk α 1/a2缺失可防止AICAR诱导的低血糖和肌肉葡萄糖摄取。Tbc 1d 1（Ser 231 Ala）敲入突变也减弱了AICAR在小鼠中的降糖作用。葡萄糖摄取和细胞表面GLUT 4含量显着较低的肌肉分离Tbc 1d 1（Ser 231 Ala）-敲入小鼠刺激后，亚最大剂量的AICAR。然而，这种Tbc 1d 1（Ser 231 Ala）-敲入突变既不损害运动诱导的肌肉葡萄糖摄取，也不影响小鼠的运动capacity in mice.Conclusions/interpretation TBC 1D 1-Ser（231）磷酸化和/或14-3-3结合部分介导AMPK调控的葡萄糖稳态和肌肉葡萄糖摄取的上下文依赖性方式。
Aims/hypothesis TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser(231), which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis.Methods Whole-body glucose homeostasis and muscle glucose uptake were assayed in mice bearing a Tbc1d1 (Ser231Ala)-knockin mutation or harbouring skeletal muscle-specific Ampk alpha 1/alpha 2 (also known as Prkaa1/2) double-knockout mutations in response to an AMPK-activating agent, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Exercise-induced muscle glucose uptake and exercise capacity were also determined in the Tbc1d1 (Ser231Ala)-knockin mice.Results Skeletal muscle-specific deletion of Ampk alpha 1/a2 in mice prevented AICAR-induced hypoglycaemia and muscle glucose uptake. The Tbc1d1(Ser231Ala)-knockin mutation also attenuated the glucose-lowering effect of AICAR in mice. Glucose uptake and cell surface GLUT4 content were significantly lower in muscle isolated from the Tbc1d1 (Ser231Ala)-knockin mice upon stimulation with a submaximal dose of AICAR. However, this Tbc1d1 (Ser231Ala)-knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice.Conclusions/interpretation TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding partially mediates AMPK-governed glucose homeostasis and muscle glucose uptake in a context-dependent manner.