Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice.
Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice.
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DOI：
10.1152/ajpregu.00358.2012
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发表时间：
2012-12
期刊：
影响因子：
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通讯作者：
T. Reynolds;Erin Merrell;Nicholas Cinquino;Megan Gaugler;L. Ng
中科院分区：
文献类型：
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作者：
T. Reynolds;Erin Merrell;Nicholas Cinquino;Megan Gaugler;L. Ng
本研究的目的是确定Akt基因消融对Akt/Forkhead Box O （FOXO）信号通路和atrogene表达的影响。这是通过研究野生型（WT）和亚型特异性Akt敲除（Akt1（-/-）和Akt2(-/-)）小鼠来完成的。与WT小鼠相比，Akt1（-/-）和Akt2（-/-）小鼠的指长伸肌（EDL）和比目鱼肌中胰岛素促进Ser（473）磷酸化的能力显著降低。与WT小鼠相比，Akt2（-/-）小鼠的EDL肌肉中总Akt1蛋白水平显著降低，这一过程似乎受到转录后调控，因为Akt1 mRNA水平不变。Akt2（-/-）小鼠的EDL肌肉中Akt1蛋白的丢失似乎不是由于胰岛素抵抗，因为4个月的高脂肪饮食未能降低WT小鼠肌肉中的Akt1蛋白水平。虽然在Akt1（-/-）和Akt2（-/-）小鼠的肌肉中FOXO3a磷酸化和atrogin1表达没有改变，但在Akt1和Akt2敲除小鼠的肌肉中atrogenes binip3和gabarapp的表达均显著升高。最后，与Akt1（-/-）和WT小鼠相比，Akt2（-/-）小鼠肌肉中Rho信号的条纹激活因子的表达显著增加。我们的研究结果表明，Akt同工异构体的消融将胰岛素作用和Akt/FOXO信号信号分离为atrogenes。
The purpose of the present study was to determine the effect of Akt gene ablation on Akt/Forkhead Box O (FOXO) signaling and atrogene expression. This was accomplished by studying wild-type (WT) and isoform-specific Akt knockout (Akt1(-/-) and Akt2(-/-)) mice. The ability of insulin to promote Akt phosphorylation on Ser(473) was significantly lower in extensor digitorum longus (EDL) and soleus muscles from Akt1(-/-) and Akt2(-/-) mice compared with WT mice. Total Akt1 protein levels were significantly lower in EDL muscles of Akt2(-/-) mice compared with WT mice, a process that appears to be posttranscriptionally regulated as Akt1 mRNA levels were unchanged. The loss of Akt1 protein in EDL muscles of Akt2(-/-) mice does not appear to be due to insulin resistance because 4 mo of a high-fat diet failed to reduce Akt1 protein levels in muscles of WT mice. Although FOXO3a phosphorylation and atrogin-1 expression were unaltered in muscles of Akt1(-/-) and Akt2(-/-) mice, the expression of the atrogenes Bnip3 and gabarapl were significantly elevated in muscles of both Akt1 and Akt2 knockout mice. Finally, the expression of striated activator of Rho signaling was significantly increased in muscles of Akt2(-/-) mice compared with Akt1(-/-) and WT mice. Our results demonstrate that the ablation of Akt isoforms disassociates insulin action and Akt/FOXO signaling to atrogenes.