Study On The Mechanism Of "Muscle-Brain Crosstalk" Of Exercise Intervention On Depression-Like Behavior In CUMS Rats Based On Metabonomics

Objective:To investigate the hippocampal metabolomic mechanism of different exercise modalities to improve depressive symptoms in CUMS rats based on 1H-NMR metabolomics,and to provide a theoretical and practical basis for the study of the "myocerebral" mechanism of exercise therapy for depression in combination with the "BDNFPGC-1α-FNDC5" signaling pathway.Crosstalk" mechanism of depression exercise therapy provides theoretical and practical basis.Methods:Thirty-five 8-week-old SD rats were randomly divided into control(C),model(D),aerobic exercise(A),resistance exercise(R)and aerobic + resistance exercise(AR)groups.Chronic unpredictable mild stress(CUMS)was used for depression modeling,and the blank control group was not administered stimulation and was housed normally.After the first 4 weeks of CUMS stimulation,the success of the rat depression model was verified by 4 behavioral indicators.The rats in the exercise group were given the corresponding exercise interventions while modeling.Group A used a wheel treadmill for aerobic exercise,group R used a weighted animal ladder for resistance exercise,and group AR combined the above two exercise methods alternately.The hippocampus and skeletal muscle tissues of rats were collected on the next day after the experiment,and the data were analyzed by 1H-NMR metabolomics technique combined with multivariate statistics,and the levels of BDNF protein in hippocampus and PGC-1α and FNDC5 protein in skeletal muscle were measured.Results:(1)Data at the end of 4 weeks of CUMS modeling showed that: compared with group C,the four behavioral assessment indexes of body weight,sugar-water preference rate,number of upright and number of crossing frames were significantly lower in groups D,A,R and AR(P<0.05,P<0.01),indicating that the CUMS model was successfully established;after 4 weeks of exercise intervention,the behavioral indexes of rats in each experimental group were still lower than those in group C(P<0.05),except for group C,there was no significant difference in rat body weight between groups,the sugar water preference rate and the number of crossing frames in groups A and R were significantly higher than those in group D,and the number of uprightness in group A was significantly higher than that in group D.(2)Compared with group C,the hippocampal mitochondria in group D were swollen,some of them were "vacuolated",some of the mitochondrial cristae were loose and broken,and the mitochondrial matrix was scattered to the corners.After the four-week exercise intervention,the mitochondrial morphology of hippocampal neurons in group A,group R and group AR was more or less normal,with tight mitochondrial cristae and uniform mitochondrial matrix compared with group D.(3)Metabolomic results showed that compared with group C,the levels of 11 metabolites,namely glutamate,alanine,creatine,phosphorylcholine,taurine,glutamine,betaine,carnosine,inositol,choline and serine,were significantly higher in the hippocampus of rats in group D(P<0.05,P<0.01);isoleucine,γ-aminobutyric acid,acetic acid,N-acetylaspartate,aspartate,dimethylamine,glycine,and lactate levels were significantly lower(P< 0.05,P<0.01);the aerobic exercise group significantly back-regulated nine metabolites,including creatine,inositol,lactate,N-acetylaspartate,taurine,glutamine,glutamate,acetic acid,and alanine;the resistance exercise group significantly back-regulated eight metabolites,including phosphorylcholine,creatine,N-acetylaspartate,taurine,aspartate,isoleucine,glycine,and γ-aminobutyric acid;aerobic + resistance exercise significantly back-regulated11 metabolites,including isoleucine,alanine,γ-aminobutyric acid,acetic acid,glutamine,N-acetylaspartate,creatine,phosphorylcholine,taurine,inositol,and glutamate.(4)The results of metabolic pathways showed that group A improved the metabolic characteristics of the hippocampus of CUMS rats mainly by regulating six metabolic pathways: alanineaspartate-glutamate metabolism,D-glutamine and D-glutamate metabolism,taurinesubtaurine metabolism,arginine biosynthesis,pyruvate metabolism and phosphatidylinositol metabolism.group R improved the metabolic characteristics of the hippocampus of CUMS rats mainly by regulating alanine-aspartate-glutamate metabolism,The AR group improved the hippocampal metabolic profile of CUMS rats by regulating alanine-aspartate-glutamate metabolism,D-glutamine-D-glutamate metabolism,taurinesubtaurine metabolism,arginine biosynthesis,phosphatidylinositol metabolism,and arginine and proline metabolism in 6 metabolic pathways to improve the hippocampal metabolic profile in CUMS rats.(5)Compared with group C,the expression of BDNF protein and PGC-1α and FNDC5 protein in hippocampus and skeletal muscle of rats in group D were significantly decreased(P<0.05,P<0.01);the expression of BDNF protein and PGC-1α and FNDC5 protein in hippocampus and skeletal muscle of rats in groups A,R and AR were significantly higher than those in group D(P<0.05,P<0.01).Conclusions:(1)Different ways of exercise can effectively improve the depressionlike behavior of CUMS rats.(2)All three exercise modes can play an antidepressant effect by regulating the metabolism of alanine-aspartic acid-glutamate and taurine-hypotaurine metabolism pathways.Among them,the degree of antidepressant effect of aerobic +resistance combined exercise is more extensive,which can adjust the upper level of 11 different metabolites in hippocampus tissue of CUMS rats.(3)The muscle-brain communication mechanism of exercise antidepressant may be related to improving the damage of hippocampal mitochondrial ultrastructure,regulating the level of hippocampus and muscle metabolites,and promoting the expression of PGC-1α-FNDC5-BDNF pathway protein in skeletal muscle and hippocampus.