Exercise training ameliorates carbon tetrachloride-induced liver fibrosis and anxiety-like behaviors.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Yuki Tomiga, Kenichi Tanaka, Joji Kusuyama, Akiko Takano, Yasuki Higaki, Keizo Anzai, Hirokazu Takahashi
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Abstract

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with mood disorders, such as anxiety, has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl4)-sedentary, and CCl4-exercise. Liver fibrosis was induced by CCl4 administration for 8 weeks, exercise was applied in the form of voluntary wheel running. After intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl4 increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl4 induced anxiety-like behavior, which was ameliorated by exercise training. In the hippocampus, CCl4-induced changes in mRNA and protein levels of factors related to anxiety, including BDNF and nNOS, were reversed by exercise. These results suggested that hepatic fibrosis-related anxiety-like behaviors are induced by excess hippocampal nNOS, and the beneficial effects of exercise were mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with anti-anxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.

运动训练可改善四氯化碳诱发的肝纤维化和焦虑样行为
慢性肝病和肝硬化与情绪失调有关。经常锻炼对包括肝脏和大脑在内的多个器官都有各种益处。然而,运动对伴有焦虑等情绪障碍的肝纤维化的治疗效果尚未进行评估。本研究评估了运动训练对肝纤维化相关焦虑样行为的影响。雄性 C57/BL6 小鼠被分为四组:车辆-静坐组、车辆-运动组、四氯化碳(CCl4)-静坐组和四氯化碳-运动组。四氯化碳(CCl4)诱导肝纤维化8周,运动形式为自愿轮跑。干预后,使用高架加迷宫评估焦虑样行为。通过血液分析、组织化学和 qRT-PCR 检测,CCl4 增加了肝脏和血清纤维化标志物,而运动训练减轻了这些变化。四氯化碳会诱发类似焦虑的行为,而运动训练可以改善这种行为。在海马中,CCl4诱导的焦虑相关因子(包括BDNF和nNOS)的mRNA和蛋白质水平的变化被运动逆转。这些结果表明,与肝纤维化相关的焦虑样行为是由海马过量的nNOS诱导的,而运动的有益作用是由BDNF的增加和nNOS的减少介导的。纤维化面积的百分比与抗焦虑行为呈负相关,与海马nNOS蛋白水平呈正相关。通过运动训练调节海马 BDNF 和 nNOS,可以缓解肝纤维化相关的焦虑样行为。这些结果支持了针对肝纤维化和相关焦虑的机制进行运动的治疗价值。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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