Study On Liver Mitochondrial Metabolomics Of Xiaoyao San In Improving Exercise Ability Of Depressed Rats

Objective: This study examined the metabolome profile of liver mitochondria in rats under chronic unpredictable mild stress(CUMS)based on LC-MS mitochondrial metabolomics,and elucidated the mechanism of action of Xiaoyao San(XYS)in improving fatigue and exercise capacity in depressed rats,and provided a theoretical and practical basis for clinical experimental research on hypokinetic depression.Methods:(1)SD rats were randomly divided into control group(C Group),model group(M Group),CUMS + Venlafaxine group(V Group)and CUMS + XYS group(X Group).Replicating the CUMS depression model,V and X groups were given the appropriate drugs by gavage for 4 weeks while modelling.Behavioral changes were detected by weight tests,open field tests,and sugar water preference tests.(2)The pole test and rotarod test are used to test exercise capacity,and biochemical indicators such as corticosterone,testosterone and blood ammonia are tested with kits.(3)The liver mitochondrial structure,ATP content and respiratory chain complex activity of CUMS rats were analyzed by transmission electron microscopy and ELISA kits.(4)This experiment examined mitochondrial samples from depressed rat liver based on LC-MS metabolomics,the data was loaded into SIMCA software for analysis.Results:(1)After 4 weeks of moulding and drug intervention,compared with C group,body weight,sugar-water preference,the number of crossing and the number of rearing in the open field test were all reduced in the rats of M group(P < 0.01).These behavioral outcomes were significantly enhanced in the rats of X and V groups compared with M group(P < 0.05).(2)After 4 weeks of moulding and drug intervention,compared with C group,the time to climb down of the pole test and the time on the bar of the rotarod test were significantly lower(P < 0.01),the serum corticosterone level was significantly increased(P< 0.01)and the testosterone and blood ammonia levels were significantly lower in M group(P < 0.05);compared with M group,the exercise capacity index and fatigue index of rats in X and V groups were significantly retuned(P < 0.05).(3)After 4 weeks of moulding and drug intervention,compared with C group,the number of mitochondria in the liver of rats was reduced,the outer membrane was blurred and the stroma was loose in M group.Compared with M group,the mitochondrial cristae in the liver of rats were clear and the structure was more complete in X group.Compared with C group,the ATP levels and respiratory chain complex I-V activities of liver mitochondria were significantly decrease in the rats of M group(P < 0.05),while the ATP levels and respiratory chain complex I and V activities were significantly enhance in rats in X and V groups compared with M group(P < 0.05).(4)Compared with C group,18 different metabolites,including malate,taurine,glutamate,etc.,were changed in the liver mitochondria in the rats of M group.Nine different metabolites,including aspartate,lactate,leucine,etc.,were back-regulated in the liver mitochondria in the rats of X group.Six metabolic pathways,including phenylalanine metabolism,glutathione metabolism,alanine,aspartate and glutamate metabolism,etc.,were involved.Conclusion: XYS significantly improved depressive behavior and enhanced exercise capacity in CUMS rats.The mechanism may be related to the effect of XYS in improving the structure and function of liver mitochondria in depressed rats and regulating metabolic pathways involved in energy and amino acid metabolism in liver mitochondria,thus improving the symptoms of fatigue.