Insulin-stimulated glucose uptake partly relies on p21-activated kinase (PAK)2, but not PAK1, in mouse skeletal muscle.
Insulin-stimulated glucose uptake partly relies on p21-activated kinase (PAK)2, but not PAK1, in mouse skeletal muscle.
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DOI：
10.1113/jp280294
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Sylow L
中科院分区：
文献类型：
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作者：
Møller LLV;Jaurji M;Kjøbsted R;Joseph GA;Madsen AB;Knudsen JR;Lundsgaard AM;Andersen NR;Schjerling P;Jensen TE;Krauss RS;Richter EA;Sylow L
I组p21活化激酶（PAK）亚型PAK1和PAK2在骨骼肌中响应胰岛素而被激活，PAK1/2信号在胰岛素抵抗小鼠和人类骨骼肌中受损。有趣的是，PAK1被认为是小鼠骨骼肌中胰岛素刺激的GLUT4易位所必需的。因此，本研究旨在进一步研究PAK1在胰岛素刺激的肌肉葡萄糖摄取中的作用。药理抑制I组PAKs， IPA-3部分降低（- 20%）胰岛素刺激的小鼠离体比目鱼肌葡萄糖摄取（p<0.001）。然而，由于没有PAK1基因单独消融的表型，因此，我们研究了PAK1和PAK2在全身葡萄糖稳态和胰岛素刺激的肌肉葡萄糖摄取中的相对需求。全身PAK1敲除（KO）、肌肉特异性PAK2 (m)KO和全身PAK1和肌肉特异性PAK2双敲除小鼠的全身呼吸交换率在很大程度上不受影响。相比之下，肌肉中缺乏PAK2的小鼠的葡萄糖耐量轻度受损，而PAK1的小鼠则没有。此外，PAK1 KO肌肉在体内和离体肌肉中表现出正常的胰岛素刺激葡萄糖摄取，而在单独缺乏PAK2（- 18%）或联合缺乏PAK1 KO（- 12%）的离体糖酵解指长伸肌中，胰岛素刺激的葡萄糖摄取略有减少（p<0.05）。综上所述，糖酵解小鼠肌肉的糖耐量和胰岛素刺激的葡萄糖摄取部分依赖于PAK2，而PAK1对于全身葡萄糖稳态和胰岛素刺激的肌肉葡萄糖摄取是不可或缺的。
The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle and PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle. Interestingly, PAK1 has been suggested to be required for insulin-stimulated GLUT4 translocation in mouse skeletal muscle. Therefore, the present investigation aimed to further examine the role of PAK1 in insulin-stimulated muscle glucose uptake. Pharmacological inhibition of group I PAKs, IPA-3 partially reduced (−20%) insulin-stimulated glucose uptake in isolated mouse soleus muscle (p<0.001). However, since there was no phenotype with genetic ablation of PAK1 alone, consequently, the relative requirement for PAK1 and PAK2 in whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake was investigated. Whole-body respiratory exchange ratio was largely unaffected in whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO and double whole-body PAK1 and muscle-specific PAK2 knockout mice. In contrast, glucose tolerance was mildly impaired in mice lacking PAK2 specifically in muscle, but not PAK1 KO mice. Moreover, while PAK1 KO muscles displayed normal insulin-stimulated glucose uptake in vivo and in isolated muscle, insulin-stimulated glucose uptake was slightly reduced in isolated glycolytic extensor digitorum longus muscle lacking PAK2 alone (−18%) or in combination with PAK1 KO (−12%) (p<0.05).In conclusion, glucose tolerance and insulin-stimulated glucose uptake partly rely on PAK2 in glycolytic mouse muscle, while PAK1 is dispensable for whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake.