| Background:According to a report released by the prestigious medical journal The Lancet in 2009, more than 90 million people in China were suffering from depression, and the number is believed to have increased since then. Exercise is considered as a treatment for depression, but mechanisms underlying its beneficial effects still remain unknown. O-Linked N-acetylglucosamine transferase (OGT) plays an important role in the post-translational modification of proteins, mediating cellular metabolism and other functions. Recent studies indicated that a targeted placental disruption of OGT impaired mitochondrial structure, metabolic process and cell redox, as well as activity of HPA axis, expression of neuropeptide Y and testosterone production, thus led to depression. OGT-dependent Milton O-GlcNAcylation links glucose metabolism to the regulation of mitochondrial motility.Objective:The current study aims to explore the interventional mechanism of OGT in depression, and the role of protein O-GlcNAacylation in the antidepressant actions of exercise.Methods:All animal procedures were carried out in accordance with the guidelines for the use of laboratory animals published by the People’s Republic of China Ministry of Health and were approved by the Experimental Animal Care and Use Committee at East China Normal University (ECNU 2006-05). Adult male (n=10) and female (n=20) Sprague-Dawley rats were housed individually in a temperature and humidity controlled vivarium with regular light-dark cycles (light on at 7:00 h and light off at 19:00 h). After 7 days, rats were mated by placing two female in the male cage. Mating was confirmed by microscopic analysis of vaginal smears for the presence of sperm the next morning. Pregnant rats were assigned randomly to control and DEX group. Dexamethasone-21-phosphate disodium salt (Sigma-Aldrich, St. Louis, MO) was dissolved in saline to achieve the concentration 0.39 mg/ml. In the last third of pregnancy (gestational day 14-21), rats were subcutaneously administered either 0.13 mg/kg dexamethasone-21-phosphate disodium salt (0.1 mg/kg DEX) or vehicle (0.9% saline) until parturition. The offspring were then trained in a swimming program or not. Rats were trained in a moderate swimming program with no weight loading in free style. Swimming exercise was performed in a class water tank (100 cm (L)×60 cm(W) ×80 cm(H)) at 32 ± 1 ℃. The depth of water was 60 cm. Exercise was performed at the same time every day. After swimming, rats were toweled dry and kept warm by electric heater. The swimming program included two phases:adaptation and training. During the first week (adaptation), the training was graded beginning with 10 min on the first day until 60 min on the last day. Then, the training period began with intensity of 60 min/day,5 days/week, for a total of 4 weeks. After swimming training, all the rats were administered behavioural test. Rats were decapitated at 12:00 p.m. to 13:00 p.m. on the day of sacrifice. The hypothalamus was rapidly and carefully isolated on ice-plate. The tissues were frozen in liquid nitrogen and then stored at -80℃ until assays. RT-PCR and Western Blotting were used to examine the gene experession.Results:(1) In the open field test, compared with the Con group, the number of poking into holes was significantly decreased in DEX rats (p<0.05); compared with the DEX group, the number of poking into holes was significantly increased in DEXS rats (p<0.05). In the tail suspension test, compared with the Con group, the struggling time was significantly decreased in DEX rats (p<0.01); compared with the DEX group, the struggling time was significantly increased in DEXS rats (p<0.01). In the sucrose consumption test, DEX group exhibited a decreased sucrose consumption compared to control group (p<0.01); in addition, DEXS group exhibited an increased sucrose consumption compared to DEX group (p<0.01). Moreover, ConS group also exhibited an increased sucrose consumption compared to Con group (p<0.05).(2) Compared with the Con group, OGT mRNA level was significantly decreased in DEX rats hypothalamus (P<0.01); compared with the DEX group, DEXS group exhibited an increased OGT mRNA level (p<0.05). Compared with the Con group, OGA mRNA level was significantly decreased in DEX rats hypothalamus (p<0.01); compared with the DEX group, DEXS group exhibited an increased OGA mRNA level (p<0.01). Compared with the Con group, ConS group also exhibited an increased OGA mRNA level (p<0.05). Moreover, ConS showed a significantly increased OGA mRNA level compared with the DEXS group (p<0.01). Compared with the Con group, OGT protein level was significantly decreased in DEX rats hypothalamus (p<0.01); compared with the DEX group, DEXS group exhibited an increased OGT protein levels (P<0.05). In addition, ConS group exhibited an increased OGA protein level compared with the DEXS group (P<0.05).(3) No significant change was observed in Milton mRNA level for all the four groups. Compared with the Con group, Syntabulin mRNA level was significantly decreased in DEX (p<0.01); Compared with the DEX group, Syntabulin mRNA level was significantly increased in DEXS (p<0.01). Compared with the Con group, there was no significant change in Syntabulin mRNA level in DEXS group. Compared with the Con group, there was a significant decrease in Miro mRNA level in ConS group (p<0.01), DEX group (p<0.01) and DEXS group (p<0.01).(4) There was no significant change in the levels of CREB mRNA and AMPK mRNA in the Con group and DEX group. Compared with the DEX and Con groups, exercise significantly increased the AMPK mRNA levels in DEXS group (p<0.05) and ConS group (p<0.05). Compared with the DEX and Con groups, exercise significantly increased the CREB mRNA level in DEXS group (p<0.01) and ConS group (p<0.05); moreover, DEXS group exhibited a decreased CREB mRNA compared to ConS group (p<0.05).Conclusion:(1) 4-week swimming exercise alleviates depression-like behaviors induced by prenatal DEX exposure.(2) Prenatal DEX exposure affects the OGT expression in rat hypothalamus, while 4-week swimming exercise reverses the change, suggesting that the O-GlcNAcylation levels in hypothalamus may be involved in the antidepressant effects of exercise.(3) Prenatal DEX exposure may damage the mitochondrial motility and disturb mitochondrial function, which can be improved by exercise.(4) Prenatal DEX exposure may influence cell metabolism and exercise can modulate cell metabolism in a positive manner.Significance:The prospective findings may contribute to our understanding of the comorbidity between depression and metabolic diseases, and suggest a new target or guide for pharmacological research and exercise intervention against depression. |
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