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首页> 外文期刊>Cellular Signalling >Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1-7) action on these pathways in cultured human myotubes
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Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1-7) action on these pathways in cultured human myotubes

机译：GSK3和MEK / ERK抑制剂对糖原合酶活性的葡萄糖依赖性调节以及血管紧张素-（1-7）对人肌管中这些途径的作用

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Glycogen synthase (GS) is activated by glucose/glycogen depletion in skeletal muscle cells, but the contributing signaling pathways, including the chief GS regulator GSK3, have not been fully defined. The MEK/ERK pathway is known to regulate GSK3 and respond to glucose. The aim of this study was to elucidate the GSK3 and MEK/ERK pathway contribution to GS activation by glucose deprivation in cultured human myotubes. Moreover, we tested the glucose-dependence of GSK3 and MEK/ERK effects on GS and angiotensin (1-7) actions on these pathways. We show that glucose deprivation activated GS, but did not change phospho-GS (Ser640/1), GSK3β activity or activity-activating phosphorylation of ERK1/2. We then treated glucose-replete and -depleted cells with SB415286, U0126, LY294 and rapamycin to inhibit GSK3, MEK1/2, PI3K and mTOR, respectively. SB415286 activated GS and decreased the relative phospho-GS (Ser640/1) level, more in glucose-depleted than -replete cells. U0126 activated GS and reduced the phospho-GS (Ser640/1) content significantly in glucose-depleted cells, while GSK3β activity tended to increase. LY294 inactivated GS in glucose-depleted cells only, without affecting relative phospho-GS (Ser640/1) level. Rapamycin had no effect on GS activation. Angiotensin-(1-7) raised phospho-ERK1/2 but not phospho-GSK3β (Ser9) content, while it inactivated GS and increased GS phosphorylation on Ser640/1, in glucose-replete cells. In glucose-depleted cells, angiotensin-(1-7) effects on ERK1/2 and GS were reverted, while relative phospho-GSK3β (Ser9) content decreased. In conclusion, activation of GS by glucose deprivation is not due to GS Ser640/1 dephosphorylation, GSK3β or ERK1/2 regulation in cultured myotubes. However, glucose depletion enhances GS activation/Ser640/1 dephosphorylation due to both GSK3 and MEK/ERK inhibition. Angiotensin-(1-7) inactivates GS in glucose-replete cells in association with ERK1/2 activation, not with GSK3 regulation, and glucose deprivation reverts both hormone effects. Thus, the ERK1/2 pathway negatively regulates GS activity in myotubes, without involving GSK3 regulation, and as a function of the presence of glucose.
机译：糖原合酶（GS）通过骨骼肌细胞中的葡萄糖/糖原消耗而被激活，但是包括主要GS调节剂GSK3在内的主要信号传导途径尚未完全确定。已知MEK / ERK途径调节GSK3并响应葡萄糖。这项研究的目的是阐明在培养的人肌管中，葡萄糖剥夺对GSK3和MEK / ERK途径对GS活化的贡献。此外，我们测试了GSK3的葡萄糖依赖性和MEK / ERK对GS的作用以及血管紧张素（1-7）在这些途径上的作用。我们显示葡萄糖剥夺激活了GS，但并未改变磷酸化GS（Ser640 / 1），GSK3β活性或ERK1 / 2的活性激活磷酸化。然后，我们分别用SB415286，U0126，LY294和雷帕霉素处理富含葡萄糖和耗尽葡萄糖的细胞，分别抑制GSK3，MEK1 / 2，PI3K和mTOR。 SB415286激活了GS，并降低了相对磷酸-GS（Ser640 / 1）的水平，在葡萄糖缺乏的情况下比葡萄糖充足的细胞更多。 U0126激活了GS，并显着降低了葡萄糖耗尽的细胞中的磷酸GS（Ser640 / 1）含量，而GSK3β活性则倾向于增加。 LY294仅使葡萄糖耗尽的细胞失活GS，而不会影响相对磷酸GS（Ser640 / 1）的水平。雷帕霉素对GS的活化没有影响。在富含葡萄糖的细胞中，血管紧张素-（1-7）提高了磷酸-ERK1 / 2的含量，但没有提高磷酸-GSK3β（Ser9）的含量，同时使GS失活并增加了Ser640 / 1上的GS磷酸化。在葡萄糖缺乏的细胞中，血管紧张素-（1-7）对ERK1 / 2和GS的作用被逆转，而相对磷酸GSK3β（Ser9）含量降低。总之，通过葡萄糖剥夺激活GS不是由于培养的肌管中的GS Ser640 / 1去磷酸化，GSK3β或ERK1 / 2调节。但是，由于GSK3和MEK / ERK的抑制，葡萄糖的消耗会增强GS激活/ Ser640 / 1的去磷酸化。血管紧张素-（1-7）失活与ERK1 / 2激活相关的葡萄糖不足细胞中的GS，而不与GSK3调控相关，并且葡萄糖剥夺可恢复两种激素的作用。因此，ERK1 / 2途径负调节肌管中的GS活性，而不涉及GSK3调节，并且是葡萄糖存在的函数。

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