Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model

doi:10.21203/rs.3.rs-2747919/v1

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Research Article

Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model

https://doi.org/10.21203/rs.3.rs-2747919/v1

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Journal Publication

published 24 Nov, 2023

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Objective

To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on ¹H-NMR metabolomics techniques, and to explore the potential mechanisms of exercise for the treatment of depression.

Methods

Rats were randomly divided into blank control group (C), CUMS control group (D), pre-exercise group (P), aerobic exercise group (A), resistance exercise group (R), and aerobic + resistance exercise group (AR). The corresponding protocol intervention was applied to each group of rats. Body weight, sucrose preference and open field tests were performed weekly during the experiment to evaluate the extent of depression in rats. Plasma samples from each group of rats were collected at the end of the experiment, and then the plasma was analyzed by ¹H-NMR metabolomics combined with multivariate statistical analysis methods to identify differential metabolites and perform metabolic pathway analysis.

Results

(1) Compared with the group D, the body weight, sucrose preference rate, and the number of crossings and standings in the different types of exercise groups were significantly improved (p < 0.05 or p < 0.01). (2) Compared to group C, a total of 15 differential metabolites associated with depression were screened in the plasma of rats in group D, involving 6 metabolic pathways. Group P can regulate the levels of 6 metabolites: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group A can regulate the levels of 6 metabolites: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose, acetoacetic acid. Group R can regulate the levels of 6 metabolites: choline, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group AR can regulate the levels of 5 metabolites: choline, citric acid, glucose, acetone, acetoacetic acid.

Conclusion

The different types of exercise groups can improve the depressive symptoms in CUMS rats, and there are common metabolites and metabolic pathways for their mechanism of effects. This study provides a powerful analytical tool to study the mechanism of the antidepressant effect of exercise, and provides an important method and basis for the early diagnosis, prevention and treatment of depression.

depression

aerobic exercise

resistance exercise

plasma

metabolomics

Depression is a neuropsychological disorder characterized by a lack of a positive attitude, low mood and a range of associated emotional, cognitive, physical and behavioral symptoms(Price and Duman, 2020). As "the epidemic of the 21st century", depression imposes enormous physical and psychological suffering on patients, as well as a huge burden on their families and society. The latest World Mental Health Report 2022 published by the World Health Organization shows that nearly one billion people in the world are suffering with mental disorders in 2019, and that the prevalence of depression has risen dramatically with the rampant development of the Corona Virus Disease 2019 in recent years(2021). It is predicted that depression will jump to the top of the list by 2030(Malhi and Mann, 2018), and there is an urgent need to find effective antidepressant treatments.

At present, the main treatments for depression are medication, exercise and psychological interventions(Marwaha et al., 2023). Medication can relieve depression, but it requires long-term medication and may cause severe side effects(Shankman et al., 2017; Sobieraj et al., 2019). Psychotherapy can also be used to improve depression, but it lacks a standardized treatment protocol and its efficacy is uncertain(Okuyama et al., 2017). Exercise therapy is based on the theories of kinesiology, neurodevelopment and biomechanics, and is designed to improve the physical and psychological state of depressed patients through the action and reaction forces of the exercise process(Kandola et al., 2019; Zhao et al., 2020). Compared to other therapies, exercise therapy has the advantages of low cost, safety and health, and no side effects, and has become the main recommended method in the treatment guidelines for depression(Schuch et al., 2016).

The primary aspect of exercise therapy is to formulate a reasonable and scientific exercise prescription. An exercise prescription consists of four main elements: type of exercise, frequency of exercise, intensity of exercise and duration of exercise(Slade and Keating, 2012). Of these, the type of exercise is the first key element to be determined, and the appropriate type of exercise should be chosen for different patients to get the best therapeutic effect. At present, the main types of exercise for depression treatment include aerobic exercise and resistance exercise(Moraes et al., 2020). There are still some issues that need to be resolved regarding exercise therapy for depression, such as whether pre-exercise has antidepressant effects, which is the most effective in improving depression, aerobic or resistance exercise, and whether a combination of the two types of exercise is better. Therefore, it is necessary further research on exercise therapy for depression.

Metabolomics is mainly focused on small molecule metabolites of molecular weight below 1000(Wishart, 2019). Metabolomics technology has developed rapidly in recent years, and researchers can use it to detect and analyze biomarkers that are closely related to diseases, which can then be used to diagnose diseases, determine the course of diseases and develop treatment options, so it plays a unique advantage in various fields of research(Newgard, 2017; Patel et al., 2022; Zhang et al., 2022). The pathogenesis of depression is complex and involves the alteration of multiple system functions(Peng et al., 2015; Suneson et al., 2021), so the antidepressant mechanism of exercise cannot be comprehensively explained from a single target. Metabolomics can study the overall metabolic changes in the human body at the level of small molecule metabolites, identifying potential biomarkers and changes in metabolic pathways(Johnson et al., 2016), providing a powerful analytical platform to explore the pathological mechanisms of depression and the antidepressant mechanisms of exercise.

In this study, we designed to replicate a rat model of depression and implement different types of exercise interventions to evaluate the antidepressant effects of different exercises through behavioral tests. The ¹H-NMR metabolomics technique was used to detect and analyze the plasma samples collected from each group of rats to identify the differential metabolites and metabolic pathways associated with the antidepressant effect of exercise. The mechanism of exercise in improving depression was elucidated at the metabolite level, with a view to providing a theoretical reference for the development and application of exercise therapy for depression from a new perspective.

Animals and ethic statement

72 Sprague-Dawley male rats (8 weeks old, weighing 210–230 g) were obtained from the Experimental Animal Center of Beijing Weitong Lihua Technology Co. Ltd. (Animal License Number: SCXK, Beijing, China, 2020-0006). The animal house was under controlled conditions of 12 h light-12 h dark cycles, temperature of 23–25℃, and relative humidity of 30–60%, and the animals had free access to rodent food and water. Animal housing and all experimental protocols were approved by the Scientific Research Ethics Committee of Shanxi University (SXULL-20200069).

Chronic unpredictable mild stress (CUMS) modeling and grouping

The rats were housed in cage for 7 days adaption to the environment before commencement of the experiment. The rats were randomly divided into six groups (n = 12 in each): 1) blank control group (C), 2) CUMS control group (D), 3) pre-exercise group (P), 4) aerobic exercise group (A), 5) resistance exercise group (R), and 6) aerobic + resistance exercise group (AR). Except group K, the rats in other groups were single caged. Rats in group C were housed normally throughout and rats in group D were exposed to chronic unpredictable stress modelling throughout. The stressors included: water deprivation, food deprivation, ice bath, ultrasonic stimulation, termal stimulus, electric shocks, tail clamp, restraint, day and night reversal. Rats in the group P were subjected to aerobic exercise for the first 4 weeks and CUMS modelling was imposed for the next 4 weeks. Rats in group A and group R were subjected to CUMS modelling for the first 4 weeks and then given the corresponding exercise for the next 4 weeks after the successful establishment of the depression model based on behavioral indicators, while still receiving CUMS modelling. The experimental design was shown in Fig. 1.

Indicators for behavioral tests

Rats in each group was evaluated by the body weight (BW), sucrose preference test (SPT) and open field test (OFT) to assess depression-like behavior at the end of each week.

1) Body weight

The body weight of each group of rats was recorded every 7 days during the experiment.

2) Sucrose preference test

The preference of rats for sugar solutions can be used as a means of assessing their pleasure deficit symptoms and depression levels. Studies have shown that 1–2% sugar water is the optimal concentration for experimental testing(Liu et al., 2018a). Each rat was placed in a separate cage and given a bottle of pure water (placed on the right side of the cage) and a bottle of 1% sugar water (placed on the left side of the cage), which were placed at the same height and in a fixed position. Sugar water preference rate = sugar water consumption (mL) / (pure water consumption + sugar water consumption) x 100%.

3) Open field test

The number of crossings and standings in the open field test are indicators of the rat's mobility and ability to explore. A laboratory-made black polyethylene open-field box (50 cm x 50 cm x 40 cm) was used and the bottom of the box was divided equally into 25 squares. The rats were placed in the box in order to explore freely for 5 min. They were acclimatized for 1 min and then their movements in the open field for the next 4 min were recorded, including the number of crossings and the number of standings.

Exercise protocols

1) Aerobic exercise

The moderate intensity aerobic exercise protocol used in this experiment was developed according to the standards of the relevant literature. To reduce the stimulation caused by unfamiliar exercise, rats in group P and group A were pre-exercised (15 minutes per day) for three days prior to the formal exercise intervention. The rats were formally exercised on a Wheeled motorized treadmill for 30 min per day, 5 times per week for 4 weeks. The treadmill speed started from 3m/min for 5min, increased to 5m/min for 5min, then to 8m/min for the last 20min.

2) Resistance exercise

Rats in group R also underwent three days of pre-exercise prior to the formal exercise intervention. The formal exercise protocol for the rats was weighted climbing 8 times a day, 5 times per week for 4 weeks. The lead pieces is wrapped around the rat's tail with tape according to its body weight. During the first week of exercise, the load was 25% of body weight and the load was increased by 25% each week until the fourth week when it was 100% of its body weight.

Plasma samples collection and preparation

After the last behavioral test, all rats were fasted but not water fasted for 12 hours and then deeply anaesthetized. The rat blood was collected into a vacuum blood collection tube containing ethylenediaminetetraacetic acid (EDTA) through an abdominal aortic method and centrifuged at 4°C, 3000 rpm for 15 min. Then, the plasma was transferred to 2 mL Eppendorf tubes and frozen at − 80°C. 450 µL of plasma sample was transferred to an Eppendorf tube after thawing and 350 µL D2O was added, then centrifuged at 13,000 rpm for 20 min at 4˚C. Finally, 600 µL of the supernatant was placed in a nuclear magnetic tube with an inner diameter of 5 mm for metabolomics.

NMR Data Acquisition and Analysis

NMR detection conditions: Bruker 600 MHz AVANCE III NMR spectrometer was used, carr-Purcell-Meiboom-Gill (CPMG) pulse sequence was adopted, parameters were set: free induction attenuation (64K data points), self-axillary relaxation delay (320ms), scanning 64 times.

NMR spectrum processing: The ¹H-NMR spectra of plasma samples from all rats were processed using the MestReNova software(Mestrelab Research, Santiago de Compostella, Spain, version 8.0.1), and the phase and baseline were adjusted with creatinine (δ3.04, - CH3) as the standard. The water peak in the region δ4.7ཞ5.2 is excluded, and the region δ0.5 ~ 5.5ppm is segmented and integrated in units of δ0.01, and the data are normalized. The data was concentrated between 0 and 1, and then the SIMCA-P 13.0 software༈Umetric, Sweden༉ was used to further process the data.

Statistical analysis

Statistical analyses were performed by two-way ANOVA followed by Dunnett’s multiple comparisons using GraphPad Prism 7.0 (GraphPad Sofware, Inc., La Jolla, CA, USA) and SPSS statistics 23.0 sofware (Chicago, IL, USA). Two groups were compared using independent samples t-test and multiple groups were compared using one-way analysis of variance.

Effects of different exercises on behavioral indicators in CUMS rats

After 4 weeks of CUMS modelling, compared with the group C, the body weight, sucrose preference rate, and the number of crossings and standings of rats in group D, group A, group R and group AR were significantly decreased (p < 0.05 or p < 0.01), indicating that the rat model of depression was established successfully. After 4 weeks of exercise intervention, depressed rats in the group A, group R and group AR showed a significant improvement in behavioral indicators (p < 0.05 or p < 0.01), indicating that both aerobic and resistance exercise have an improving effect on depressive behavior. Interestingly, we found that the group P, due to 4 weeks of prior aerobic exercise, resulted in some delay in the onset of depressive behavior in CUMS rats.

Plasma metabolomics of each group

Plasma NMR spectrum

A typical ¹H-NMR spectrum of plasma in group D is shown in Fig. 3. The NMR data were analyzed by chemical shifts, coupling constants, and peak patterns, with reference to literature reports, and in combination with Chenomx NMR Suite software (Chenomx Inc, Edmonton, AB, Canada). A total of 24 endogenous metabolites were identified, including amino acids, choline and inositol.

Multivariate statistical analysis

In order to more visually distinguish the metabolic profiles of each group of rats, this study firstly used the unsupervised PCA model to downscale and preliminary analyze the sample data of each group to remove outliers. Supervised OPLS-DA model analysis was then performed on sample data to obtain OPLS-DA score scatter plots and model validation plots, which are shown in Figs. 3.1c and 3.1d.

As can be seen from the PCA score plot, group C and group D are significantly separated, indicating that CUMS modelling has an effect on the plasma metabolic profile in the rat. The quality of PLS-DA model was evaluated by R2 and Q2. Then, OPLS-DA analysis was performed on group C and group D, VIP values were combined with S-plot (Fig. 4d and 5d). According to VIP > 1 and p < 0.05, a total of 15 qualified metabolites with significant differences were detected in the plasma of depressed rats. Then the differential metabolites were analyzed by one-way ANOVA. As shown in Fig, The levels of glucose and phosphocreatine in the group D were significantly reduced compared to group C, while the levels of isoleucine, valine, low density lipoprotein, N-acetylglycoprotein, β-hydroxybutyric acid, acetone, choline, glycine, leucine, lactate, acetoacetic acid, citric acid and inositol were significantly increased. These differential metabolites are mainly related to energy metabolism, lipid metabolism and amino acid metabolism.

Prior pre-exercise can regulate the levels of 6 metabolites associated with depression: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. After aerobic exercise intervention, the levels of 6 metabolites associated with depression were significantly back-regulated: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose, acetoacetic acid. After resistance exercise intervention, the levels of 6 metabolites associated with depression were significantly back-regulated: choline, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. After aerobic exercise in combination with resistance exercise intervention, the levels of 5 metabolites associated with depression were significantly back-regulated: choline, citric acid, glucose, acetone, acetoacetic acid.

Pathway analysis

The metabolic pathway enrichment analysis allows for a better understanding of the internal linkages between metabolites. Each circle symbolizes a metabolic pathway and the size and color of the circle is positively correlated with the Impact value of the metabolic pathway. The 15 metabolites screened that were associated with depression, as well as metabolites that were significantly back-regulated after different exercises were imported into the Metaboanalyst 5.0 database for metabolic pathway analysis.

With the Impact value > 0.1, 6 metabolic pathways significantly associated with depression were obtained: synthesis and degradation of ketone bodies, valine, leucine and isoleucine biosynthesis, glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, butanoate metabolism, inositol phosphate metabolism. Pre-exercise improves plasma metabolism in depressed rats by modulating synthesis and degradation of ketone bodies, butanoate metabolism and inositol phosphate metabolism. Aerobic exercise improves plasma metabolism in depressed rats by regulating synthesis and degradation of ketone bodies, butanoate metabolism and valine, leucine and isoleucine biosynthesis. Resistance exercise improves plasma metabolism in depressed rats by modulating synthesis and degradation of ketone bodies, butanoate metabolism and inositol phosphate metabolism. Aerobic exercise combined with resistance exercise improved plasma metabolism in depressed rats mainly by modulating synthesis and degradation of ketone bodies, butanoate metabolism, glyoxylate and dicarboxylate metabolism.

In this study, a rat model of depression was successfully established by 4 weeks of CUMS stimulation. We intervened with four exercise protocols in CUMS rats and observed the changes in behavioral indicators in each group. Then, ¹H-NMR metabolomics was used to detect and analyze the changes in plasma metabolites in each group of rats, and a total of 15 metabolites associated with depression were screened. Group P can regulate the levels of 6 depressive metabolites. Group A can regulate the levels of 6 depressive metabolites. Group R can regulate the levels of 6 depressive metabolites. Group AR can regulate the levels of 5 depressive metabolites. Interestingly, there are metabolites that are co-regulated by different types of exercise groups in terms of improving depression(Fig. 7).

Effects of different types of exercise on the behaviors of depressed rats

Animal models of CUMS-induced depression can imitate the core symptoms of human depression(Antoniuk et al., 2019; Hao et al., 2019), and thus are more widely used than other depression models to study antidepressant mechanisms(Li et al., 2021; Liu et al., 2018b). After behavioral tests, it was found that the CUMS rats in this experiment showed significant weight loss, reduced active and exploratory behaviors, lack of pleasure and other typical depressive symptoms, indicating the successful reproduction of our animal model.

Depression can lead to a wasting of body mass and a dramatic loss of weight. The results of this experiment showed a significant slowing of weight gain in CUMS rats and no significant increase in body weight after different types of exercise. It is speculated that this may be due to energy consumption as a result of exercise, indicating that body weight status cannot be used as a valid indicator of the antidepressant effect of exercise.

Decreased mobility is a major behavioral symptom of depression, and the open field experiment can visualize the spontaneous activity behavior of experimental animals. The results of this experiment showed that the number of crossings and the number of standings in CUMS rats were both significantly reduced. After different types of exercise, the number of crossings and the number of standings in CUMS rats significantly increased, indicating that exercise can effectively improve the activity of rats. Notably, aerobic exercise had a better antidepressant effect compared to resistance exercise.

The pleasure deficit is a key symptom of depression, and depressed animals usually show a reduction in sucrose preference rate. The results of this experiment showed that the sugar-water preference rate was significantly reduced in CUMS rats, and that different exercises were effective in alleviating the pleasure deficit in depressed rats.

In summary, different types of exercises have positive antidepressant effects, in which aerobic exercise has a broader effect than resistance exercise. It is necessary to explore their potential antidepressant mechanisms in depth, so as to better serve the depressed patients.

Metabolic modulation of the antidepressant effect of aerobic exercise

Ketone bodies are intermediate products of fatty acid catabolism and oxidation, including acetoacetic acid, acetone and β-hydroxybutyric acid, which have a protective effect on the central nervous system(Evans et al., 2017). At a normal state the body does not break down fat to produce ketone bodies, only a relative lack of energy, usually when sugar is insufficient or cannot be used efficiently, and the body will break down fat to produce ketone bodies. Some studies have shown that ketone bodies can increase the level of γ-aminobutyric acid(GABA), which is an inhibitory neurotransmitter that is helpful in reducing stress and lowering anxiety(Brietzke et al., 2018). In addition, ketone bodies can increase the level of glutathione (an important antioxidant) and reduce the level of free radicals, thereby improving mitochondrial function and alleviating the depressive symptoms caused by chronic oxidative stress(Zalachoras et al., 2020). In the present study, the levels of acetoacetic acid, acetone and β-hydroxybutyric acid in the plasma of CUMS rats were significantly reduced, while all exercise groups could modulate the levels of acetoacetic acid and the group AR could also modulate the levels of acetone, suggesting that exercise could have antidepressant effects by regulating the synthesis and degradation of ketone bodies.

Citric acid is an endogenous metabolite associated with the transfer of cellular energy, which can effectively reduce oxidative stress in the body and promote metabolism through the TCA cycle(Setoyama et al., 2016; Zalachoras et al., 2020). Some studies suggested that the level of citric acid can affect different hormones in the body (e.g., adrenocorticotropic hormone, epinephrine, norepinephrine) which are closely associated with psychiatric disorders, especially depression, so citric acid may be a key "regulator" of emotions(Delcourt et al., 2017). Glucose is the major source of energy as well as the main energy substrate for neurons and glial cells, which is important for the neuronal microenvironment(Tang, 2020). It has been found that prolonged poor control of glucose in the body can cause structural and functional damage to brain areas such as the hypothalamus and hippocampus, which can lead to depression(Diepenbroek et al., 2013). Lactate is the final product of glucose metabolism under anaerobic conditions(Rabinowitz and Enerbäck, 2020). The increased level of lactate in the plasma of depressed patients indicates an inhibition of glucose metabolism (glycolysis and glucose oxidation pathways) and this inhibition may be related to anaerobic cellular respiration, an energy metabolic process that indicates a reduced metabolic capacity(Yuan et al., 2011). In the results of our experiments, the levels of glucose, lactate and citric acid in the plasma of CUMS rats were abnormal, suggesting a disruption of energy metabolism, and energy deficiency can lead to depressive symptoms, such as less activity, increased fatigue and cognitive dysfunction. After intervention of exercise, all exercise groups can modulate the level of glucose, and group A, group P and group R can also modulate the level of lactate, and group AR can also modulate the level of citric acid, indicating that exercise can effectively modulate the abnormal metabolites associated with energy metabolism in depression.

Amino acids are the basic units of protein molecules, which are closely related to the life activities of organisms and are one of the most essential substances in the body(Stollar and Smith, 2020). Isoleucine, leucine and valine are generically known as branch chain amino acids (BCAAs), which cross the blood-brain barrier and compete with the precursor of 5-HT — tryptophan(Baranyi et al., 2016; Sperringer et al., 2017). When the levels of BCAAs are decreased, they will interfere with the release of 5-HT in the brain, which in turn leads to the fatigue of the nervous system(Blomstrand, 2006). In the present study, the levels of leucine, isoleucine and valine in the plasma of CUMS rats were all significantly decreased, while the levels of leucine and valine could be back-regulated after pre-exercise and aerobic exercise, suggesting that exercise may improve the fatigue symptoms of depression by modulating the levels of BCAAs. Choline plays an important role in neurotransmission and its abnormal levels may lead to the cognitive impairments that are associated with neurodegenerative and neuropsychiatric disorders(Sarter and Parikh, 2005). The increased level of choline in the plasma of depressed rats indicates that a dysfunction in plasma metabolism related to lipoproteins and phospholipids was induced, which is consistent with the results of studies in the relevant literature(Liu et al., 2015). Exercise can increase the immunity of the body by regulating the level of N-acetylglycoprotein content in plasma(Scheffer and Latini, 2020).

In the nervous system, inositol acts as a second messenger, affecting the balance of neurotransmitter function, and plays an important role in maintaining glial cell function and regulating synaptic activity(Cao et al., 2013). Some clinical studies have shown that inositol can improve depression, anxiety and other mental disorders by stimulating hormones such as 5-HT and dopamine(Chiappelli et al., 2015; Taylor et al., 2004). In this study, the level of inositol was significantly reduced in the plasma of CUMS rats and significantly increased after pre-exercise and resistance exercise, suggesting that exercise can improve depression by modulating the level of inositol in the organism. Phosphocreatine can break down to creatinine without the involvement of enzymes. Phosphocreatine has the function of storing excess ATP(Ament and Verkerke, 2009). Creatinine is an important substance involved in energy metabolism and also regulates neuroexcitation in the body, which is closely related to depression(Liu et al., 2022; Pu et al., 2021).

Different types of exercise can effectively improve the depressive behavior of CUMS rats, and aerobic exercise has a broader effect than resistance exercise. In addition, pre-exercise can effectively prevent the onset of depression. The pathogenesis of depression is closely associated with the disturbance of metabolism in the body and exercise can improve depression by regulating specific metabolites and metabolic pathways. And different types of exercise have the same metabolites and metabolic pathways in regulating the group of depression-related metabolites.

Funding This work was supported by the Project of Natural Science Research in Shanxi Province, China (202103021224027).

Competing interests All authors declare that they have no competing interests.

Availability of data and material All data generated or analyzed during this study are included in this published article.

Authors' contributions Y.H., B.Z., X.L., and J.T. conceived and supervised the study; B.Z., and X.L. performed the experiments; B.Z., and X.L. analyzed the data and drafted the manuscript; S.Z. reviewed and edited the manuscript. All authors read and approved the final version of the manuscript.

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Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model

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