The 5′-AMP-activated protein kinase γ3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle
The 5′-AMP-activated protein kinase γ3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle
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DOI：
10.1074/jbc.m405533200
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发表时间：
2004-09-10
影响因子：
4.8
通讯作者：
Andersson, L
中科院分区：
文献类型：
--
作者：
Barnes, BR;Marklund, S;Andersson, L
5'-AMP激活的蛋白激酶（AMPK）是所有真核生物中存在的代谢应激传感器。 PIG PRKAG3中的主要错义突变（R225Q），编码肌肉特异性γ3同工型，导致糖原含量显着增加。为了确定AMPKγ3同工型的功能作用，我们产生了具有骨骼肌肉特异性表达的野生型或突变体（225q）小鼠gamma3以及Prkag3敲除小鼠的转基因小鼠。运动后的糖原在AMPKγ3敲除小鼠中受损，并在转基因突变小鼠中显着增强。 AMPK激活剂未能增加AMPKγ3敲除小鼠中骨骼肌葡萄糖的吸收，而收缩效果则保留了。当放置高脂肪饮食时，可以保护转基因突变小鼠而不是敲除小鼠，以防止骨骼肌中过度的甘油三酸酯积累和胰岛素抵抗。转染实验表明R225Q突变与较高的基础AMPK活性和AMP依赖性降低有关。我们的结果验证了肌肉特异性AMPKγ3同工型，作为预防和治疗胰岛素抵抗的治疗靶标。
5'-AMP-activated protein kinase (AMPK) is a metabolic stress sensor present in all eukaryotes. A dominant missense mutation (R225Q) in pig PRKAG3, encoding the muscle-specific gamma3 isoform, causes a marked increase in glycogen content. To determine the functional role of the AMPK gamma3 isoform, we generated transgenic mice with skeletal muscle-specific expression of wild type or mutant (225Q) mouse gamma3 as well as Prkag3 knockout mice. Glycogen resynthesis after exercise was impaired in AMPK gamma3 knock-out mice and markedly enhanced in transgenic mutant mice. An AMPK activator failed to increase skeletal muscle glucose uptake in AMPK gamma3 knock-out mice, whereas contraction effects were preserved. When placed on a high fat diet, transgenic mutant mice but not knock-out mice were protected against excessive triglyceride accumulation and insulin resistance in skeletal muscle. Transfection experiments reveal the R225Q mutation is associated with higher basal AMPK activity and diminished AMP dependence. Our results validate the muscle-specific AMPK gamma3 isoform as a therapeutic target for prevention and treatment of insulin resistance.