運動對FOXO1及相關訊息調控因子之影響

The Effect of Exercise-induced FOXO1 and Related Signal Transduction in Rat

謝智凱(Chih-Kai Hsieh) ； 郭家驊(Chia-Hua Kuo)

《大專體育學術專刊》 97年度 (2008/05) Pp. 775-783

https://doi.org/10.6695/AUES.200805_97.0113

摘要

背景：Forkhead family亦稱為「Forkhead box」，其主要功能是與DNA結合，進而啟動下游基因做出反應，以維持生物體之恆定。FOXO1為Forkhead family一員，該轉錄因子影響細胞的功能非常多，包括：影響細胞週期、修復DNA損傷、細胞凋亡、與排除氧化壓力等，因此FOXO1在細胞生理方面扮演極重要之角色。運動會造成氧化自由基增加，而氧化自由基促使結合在DNA表面的8-OH-dg產量增加，因此8-OH-dg可用來作為DNA損傷的生物指標。過去文獻指出氧化自由基會經由MAPK路徑活化FOXO１，因此本研究探討運動增加氧化自由基是否活化FOXO1以及相關訊息傳遞路徑。方法：將40隻雄性大鼠分為控制組（C）、運動一小時組（1E）、運動三小時組（3E0）、運動三小時後恢復一小時組（ER）並加以游泳訓練，觀察肺臟組織RNA及磷酸化蛋白FOXO1、JNK、Akt及8-OH-dg之變化。結果：1E與3E組磷酸化FOXO1蛋白顯著降低，運動組之磷酸化JNK與DNA上8-OH-dg的量顯著增加，Akt則無顯著差異。結論：運動組包括1E、3E之磷酸化FOXO1較控制組均呈現有意義的下降，運動組隨著運動時間的增長，1E、3E與ER各組動物之DNA較控制組動物DNA有較多的ROS之生物標記8-OH-dg的增加。在訊息傳遞方面，運動所造成肺部ROS的損傷及磷酸化FOXO1的減少，並非透過PI3K/Akt訊息傳導路徑，而可能是藉由MAPK/JNK磷酸化增加的方式將訊息傳遞到核內。

關鍵字

自由基

並列摘要

Background: Forkhead family is also known as ”Forkhead box”, and its major function is binding to DNA and activating the downstream genes to maintain homeostasis. FOXO1 is a member of the Forkhead family, which belongs to transcriptional factors in mammalian cells. FOXO1 regulates a plethora of cellular and physiological functions including cell cycle regulation, DNA repair, cell apoptosis, scavenging reactive oxygen species (ROS). As a result, FOXO1 plays an important role in cell for defending stress. It's well known that exercise could cause ROS accumulation, and ROS would promote FOXO1 translocation into nucleus. Therefore, we investigated whether exercise would influence FOXO1 expression, and explored clarified its underlying mechanism. Material and Methods: 40 male SD rats were divided into 4 groups: control group (C), exercise for 1 hr (1E), exercise for 3 hr (3E), exercise for 3 hr and recovery 1 hr (ER). After swimming exercise for an indicated time, we collected lung sample, and extracted cellular RNA and protein to observe total and phosphorylated protein of FOXO1, JNK and Akt. We also extracted DNA to detect ROS biomarker 8-OH-dg. Result: Exercise did not alter FOXO1 mRNA expression. However, phosphorylated-FOXO1 protein expression was significantly decreased in group 1E and 3E, compared to group C. In ROS damage assay, we found that DNA extract in 1E, 3E, and ER group showed markly increased 8-OH-dg expression. Moreover, phosphorylated-JNK, PI3K/Akt pathway was significantly increased in exercised groups but not. Conclusion: Exercise decreased phosphorylated-FOXO1 protein level without increasing its mRNA expression, and enhanced 8-OH-dg DNA marker in a dose-dependent manner in rat lungs. At the molecular level, exercise caused FOXO1 dephosphorylation and lung damage via ROS generation through MAPK/JNK signaling pathway, but not via PI3K/Akt.

並列關鍵字

ROS ； FKHR ； 8-OH-dg