NAD+-dependent SIRT4 has been reported to be a key regulator of metabolic enzymes and antioxidant defense mechanisms in mitochondria. It also plays an important role in regulation of mitochondrial metabolism in response to exercise. Recent studies have shown that SIRT4 is involved in a wide range of mitochondrial metabolic processes, including depressing insulin secretion in pancreatic beta cells, promoting lipid synthesis, regulating mitochondrial adenosine triphosphate (ATP) homeostasis, controlling apoptosis and regulating redox. SIRT4 also appears to have enzymatic functions involved in posttranslational modifications such as ADP-ribosylation, lysine deacetylation and lipoamidation. However, the effects on SIRT4 by metabolic diseases and changes in metabolic homeostasis such as during exercise, along with the roles of SIRT4 in the regulation of metabolism during disease, are not well understood. The main goal of this review is to critically analyse and summarise the current research evidence on the significance of the SIRT4 as a metabolic regulator and in mitochondrial function and its putative roles in relation to metabolic diseases and exercise.

It is known that bioenergetics of aerobic and resistance exercise are not the same but both can effectively improve depression. However, it is not clear whether and how different types of exercise can influence depression through the same metabolic regulatory system. Metabolomics provides a way to study the correlation between metabolites and changes in exercise and/or diseases through the quantitative analysis of all metabolites in the organism. The objective of this study was to investigate the effects of aerobic and resistance training on urinary metabolites by metabolomics analysis in a rodent model of depression. Male Sprague-Dawley rats were given chronic unpredictable mild stress (CUMS) for eight weeks. The validity of the modeling was assessed by behavioral indices. After four weeks of CUMS, the rats that developed depression were randomly divided into a depression control group, an aerobic training group and a resistance training group. There was also a normal control group. From week 5, the rats in the exercise groups were trained for 30 min per day, five days per week, for four weeks. The urine samples were collected pre and post the training program, and analyzed by proton nuclear magnetic resonance (¹H-NMR) spectroscopy. Both types of training improved depression-like behavior in CUMS rats. Compared with normal control, 21 potential biomarkers were identified in the urine of CUMS rats, mainly involved in energy, amino acids and intestinal microbial metabolic pathways. Common responses to the training were found in the two exercise groups that the levels of glutamine, acetone and creatine were significantly recalled (all P<0.05) Aerobic training also resulted in changes in pyruvate and trigonelline, while resistance training modified α-Oxoglutarate, citric acid, and trimethylamine oxide (all P<0.05). Aerobic and resistance training resulted in common effects on the metabolic pathways of alanine-aspartate-glutamate, TCA cycle, and butyric acid. Aerobic training also had effects on glycolysis or gluconeogenesis and pyruvate metabolism, while resistance training had additional effect on intestinal microbial metabolism.

This study analyzed the effects of aerobic exercise on endogenous serum metabolites in response to chronic unpredictable mild stress (CUMS) using a rat model, aiming to identify the metabolic regulatory pathways involved in the antidepressant effect resulted from a 28-day treadmill aerobic exercise intervention. The animals were randomly divided into four groups (n = 8): normal control, normal with aerobic exercise, CUMS control, and CUMS with aerobic exercise. Body weight, sucrose preference and open field tests were performed weekly during the intervention period for changes in depressant symptoms. Serum metabolic profiles obtained by using the LC–MS/MS metabolomics were analyzed to explore the regulatory mechanism for the effect of the aerobic exercise on depression. Behavior tests showed that the aerobic exercise resulted in a significant improvement in depression-like behavior in the CUMS rats. A total of 21 differential metabolites were identified as being associated with depression in serum metabolic profile, of which the aerobic exercise significantly modulated 15, mainly related to amino acid metabolism and energy metabolism. Collectively, this is the first study that LC–MS/MS techniques were used to reveal the modulatory effects of aerobic exercise on the serum metabolic profile of depressed rats and the findings further enriched our understanding of potential mechanisms of aerobic exercise interventions on depression.

The objectives of this study were to compare the antidepressant effects between endurance and resistance exercise for optimizing interventions and examine the metabolomic changes in different types of skeletal muscles in response to the exercise, using a rat model of chronic unpredictable mild stress (CUMS)-induced depression. There were 32 male Sprague-Dawley rats randomly divided into a control group (C) and 3 experimental groups: CUMS control (D), endurance exercise (E), and resistance exercise (R). Group E underwent 30 min treadmill running, and group R performed 8 rounds of ladder climbing, 5 sessions per week for 4 weeks. Body weight, sucrose preference, and open field tests were performed pre and post the intervention period for changes in depressant symptoms, and the gastrocnemius and soleus muscles were sampled after the intervention for metabolomic analysis using the ¹H-NMR technique. The results showed that both types of exercise effectively improved the depression-like symptoms, and the endurance exercise appeared to have a better effect. The levels of 10 metabolites from the gastrocnemius and 13 metabolites from the soleus of group D were found to be significantly different from that of group C, and both types of exercise had a callback effect on these metabolites, indicating that a number of metabolic pathways were involved in the depression and responded to the exercise interventions.

Depression accounts for 10% of the total global burden of nonfatal disease. Xiaoyao Powder, a well-known traditional Chinese medicine is commonly used to treat depression. However, its therapeutic mechanisms have not yet been fully elucidated. In this study, a rat depression model was established by the application of chronic unpredictable mild stress (CUMS). The depressed rats were randomly distributed to four groups: Blank Control, CUMS control, CUMS with Venlafaxine (a positive control) treatment, and CUMS with Xiaoyao Powder treatment, with 12 rats in each group. Depression behavioral and exercise tests were performed weekly during the four-week intervention. Stable isotope tracer metabolomics and molecular biology techniques were utilized to determine the changes in serum metabolites pre and post the intervention period, aiming to elucidate the mechanism of Xiaoyao Powder in improving the depression symptoms and exercise capacity of the depressed rats. The results found that the Xiaoyao Powder treatment significantly improved the performance in the behavioral and exercise tests, as well as affected the levels of metabolites, such as pyruvic acid, lactic acid, and citric acid in serum. It was concluded that Xiaoyao Powder intervention had a significant effect on the pyruvic acid metabolism, glycolysis/gluconeogenesis, and tricarboxylic acid cycle in the serum of the depressed rats, which could contribute to the understanding of the mechanism of the intervention. GRAPHICAL ABSTRACT