FoxO1 signaling plays a pivotal role in the cardiac telomere biology responses to calorie restriction.
FoxO1 signaling plays a pivotal role in the cardiac telomere biology responses to calorie restriction.
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DOI：
10.1007/s11010-015-2615-8
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发表时间：
2016-01
影响因子：
4.3
通讯作者：
Furuyama T
中科院分区：
文献类型：
--
作者：
Makino N;Oyama J;Maeda T;Koyanagi M;Higuchi Y;Shimokawa I;Mori N;Furuyama T
本研究探讨了在热量限制（CR）过程中，O组1（FoxO1）的叉头转录因子是否可能参与端粒生物学。我们使用FoxO1基因敲除的杂合子小鼠（FoxO1 +/−）和野生型小鼠（WT）作为对照。WT和FoxO1 +/−均从15周龄开始接受自由采食（AL）或与AL相比30% CR 20周。在研究结束时，所有组小鼠的心脏与体重比、血糖和血脂特征均无差异。FoxO1 +/−-AL中的端粒大小显著低于WT-AL，并且在WT-CR或FoxO1 +/−-CR中均未观察到端粒磨损。端粒酶活性在WT-CR的心脏和肝脏中升高，但在FoxO1 +/−-CR的心脏和肝脏中没有升高。WT-CR和FoxO1 +/−-CR心肌组织中Akt磷酸化被抑制，Sirt 1被激活。然而，在WT-CR中，与胞质轻链3结合的比例增加，p62水平降低，但在FoxO1 +/−-CR中没有。氧化性DNA损伤的标志物8-OhdG仅在WT-CR中显著降低。在WT-CR中，MnSOD和eNOS水平升高，而切割的caspase-3水平降低，但FoxO1 +/−-CR没有。超声心动图显示，WT-CR或FoxO1 +/−-CR的左心室舒张末期和收缩末期尺寸分别显著低于WT-AL或FoxO1 +/−-AL。目前的研究表明，FoxO1通过诱导参与端粒酶活性的基因，以及在CR条件下的抗氧化，自噬和抗凋亡基因发挥有益的作用，并表明FoxO1信号转导可能是CR期间代谢平衡的重要介导剂。
This study examined whether the forkhead transcription factors of O group 1 (FoxO1) might be involved in telomere biology during calorie restriction (CR). We used FoxO1-knockout heterozygous mice (FoxO1+/−) and wild-type mice (WT) as a control. Both WT and FoxO1+/− were subjected to ad libitum (AL) feeding or 30 % CR compared to AL for 20 weeks from 15 weeks of age. The heart-to-body weight ratio, blood glucose, and serum lipid profiles were not different among all groups of mice at the end of the study. Telomere size was significantly lower in the FoxO1+/−-AL than the WT-AL, and telomere attrition was not observed in either WT-CR or FoxO1+/−-CR. Telomerase activity was elevated in the heart and liver of WT-CR, but not in those of FoxO1+/−-CR. The phosphorylation of Akt was inhibited and Sirt 1 was activated in heart tissues of WT-CR and FoxO1+/−-CR. However, the ratio of conjugated to cytosolic light chain 3 increased and the level of p62 decreased in WT-CR, but not in FoxO1+/−-CR. A marker of oxidative DNA damage, 8-OhdG, was significantly lower in WT-CR only. The level of MnSOD and eNOS increased, and the level of cleaved caspase-3 decreased in WT-CR, but not FoxO1+/−-CR. Echocardiography showed that the left ventricular end-diastolic and systolic dimensions were significantly lower in WT-CR or FoxO1+/−-CR than WT-AL or FoxO1+/−-AL, respectively. The present studies suggest that FoxO1 plays beneficial roles by inducing genes involved in telomerase activity, as well as anti-oxidant, autophagic, and anti-apoptotic genes under conditions of CR, and suggest that FoxO1 signaling may be an important mediator of metabolic equilibrium during CR.