The role and mechanism of the kynurenine/kynuric acid pathway in the muscles of mice with primary biliary cholangitis and fatigue
Objective To investigate the role and mechanism of the kynurenine/kynuric acid(KYN/KYNA)path-way in the muscles of mice with primary biliary cholangitis and fatigue.Methods Twelve mice were randomly divided into control group,DDC group,DDC+depression group,DDC+depression+Clomipramine group,with 3 mice in each group.The control group was fed with conventional feed,while the DDC+depression group and DDC+depression+Clomi-pramine group were subjected to chronic unpredictable mild stress to replicate mice depression models.Two weeks later,the DDC group,DDC+depression group and DDC+depression+Clomipramine group began to continuously feed with feed containing 0.1％of DDC to establish a bile stasis model.At the same time,the DDC+depression+Clomipramine group was intraperitoneally injected with Clomipramine hydrochloride(7.5 mg·kg-1·d-1)for 14 consecutive days,while the other groups of mice were intraperitoneally injected with physiological saline.Observe and record changes in mice body mass.Conduct a weight-bearing swimming test and record the weight-bearing swimming time of each group of mice.Evaluate the depression effect in mice using forced swimming and tail suspension test.ELISA was used to detect the changes in serum and muscle levels of KYN and KYNA in each group of mice.Take the liver and muscles for HE stai-ning,and observe the pathological changes in the liver and muscle tissues.Use ROS staining to analyze the degree of muscle oxidative damage.Results Compared with the control group,the DDC group,DDC+depression group and DDC+depression+Clomipramine group mice showed significant fatigue and depressive like behavior(P＜0.05).Compared with the DDC group,the DDC+depression group showed increased fatigue and depressive like behavior(P＜0.05).The fatigue and depression in the DDC+depression+Clomipramine group were reduced compared with the DDC+depression group(P＜0.05).The HE staining results of mice liver and muscle tissues showed that compared to the control group,the DDC group,DDC+depression group and DDC+depression+Clomipramine group exhibited varying degrees of patho-logical damage.The pathological damage of liver and muscle tissues in the DDC+depression+Clomipramine group mice was reduced compared to the DDC+depression group.Compared with the control group,the ROS content in the muscles of mice in the DDC group,DDC+depression group and DDC+depression+Clomipramine group showed varying degrees of increase.Compared with the DDC+depression group,the ROS content in the muscles of mice in the DDC+depression+Clomipramine group was significantly reduced.Compared with the control group,the serum and muscle KYN levels of mice in the DDC group,DDC+depression group and DDC+depression+Clomipramine group were significantly increased(P＜0.05),while KYNA levels were significantly decreased(P＜0.05).The concentration of KYN in serum and mus-cle of mice in the DDC+depression group was significantly higher than that in the DDC group(P＜0.05).The concen-tration of KYN in the serum and muscle of mice in the DDC+depression+Clomipramine group was significantly lower than that in the DDC+depression group(P＜0.05).Conclusion The KYN/KYNA pathway has a regulatory effect on periph-eral fatigue in mice with primary biliary cholangitis accompanied by fatigue,and antidepressant therapy can improve muscle fatigue.
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