有氧运动通过调节血清外泌体中的 MALAT1/miR-382-3p/BDNF 信号通路改善 2 型糖尿病小鼠的认知障碍。
Aerobic exercise improves cognitive impairment in mice with type 2 diabetes by regulating the MALAT1/miR-382-3p/BDNF signaling pathway in serum-exosomes.
机构信息
National Clinical Research Center for Geriatric Disorders, Department of Rehabilitation, Xiangya Hospital Central South University, Changsha, 410008, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Department of Neurology, Xiangya Hospital Central South University, Changsha, 410008, China.
出版信息
Mol Med. 2023 Sep 22;29(1):130. doi: 10.1186/s10020-023-00727-1.
BACKGROUND
It has been documented that aerobic exercise (AE) has a positive effect on improving cognitive function in type 2 diabetes (T2DM) patients. Here, we tried to explore how AE regulates the expression of long non-coding RNA in serum-exosomes (Exos), thereby affecting cognitive impairment in T2DM mice as well as its potential molecular mechanism.
METHODS
T2DM mouse models were constructed, and serum-Exos were isolated for whole transcriptome sequencing to screen differentially expressed lncRNA and mRNA, followed by prediction of downstream target genes. The binding ability of miR-382-3p with a long non-coding RNA MALAT1 and brain-derived neurotrophic factor (BDNF) was explored. Then, primary mouse hippocampal neurons were collected for in vitro mechanism verification, as evidenced by the detection of hippocampal neurons' vitality, proliferation, and apoptosis capabilities, and insulin resistance. Finally, in vivo mechanism verification was performed to assess the effect of AE on insulin resistance and cognitive disorder.
RESULTS
Transcriptome sequencing analysis showed that MALAT1 was lowly expressed and miR-382-3p was highly expressed in serum-Exos samples of T2DM mice. There were targeted binding sites between MALAT1 and miR-382-3p and between miR-382-3p and BDNF. In vitro experiments showed that MALAT1 upregulated BDNF expression by inhibiting miR-382-3p. Silencing MALAT1 or overexpressing miR-382-3p could reduce the expression of INSR, IRS-1, IRS-2, PI3K/AKT, and Ras/MAPK, inhibit neuronal proliferation, and promote apoptosis. In vivo experiments further confirmed that AE could increase the expression of MALAT1 in serum-Exos to competitively inhibit miR-382-3p and upregulate BDNF expression, thereby improving cognitive impairment in T2DM mice.
CONCLUSION
AE may upregulate the expression of MALAT1 in serum-Exos to competitively inhibit miR-382-3p and upregulate BDNF expression, thus improving cognitive impairment in T2DM mice.
背景
有文献记载，有氧运动（AE）对改善 2 型糖尿病（T2DM）患者的认知功能有积极影响。在这里，我们试图探讨 AE 如何调节血清外泌体（Exos）中长链非编码 RNA 的表达，从而影响 T2DM 小鼠的认知障碍及其潜在的分子机制。
方法
构建 T2DM 小鼠模型，分离血清 Exos 进行全转录组测序，筛选差异表达的 lncRNA 和 mRNA，预测下游靶基因。探讨 miR-382-3p 与长链非编码 RNA MALAT1 和脑源性神经营养因子（BDNF）的结合能力。然后，收集原代小鼠海马神经元进行体外机制验证，通过检测海马神经元活力、增殖和凋亡能力以及胰岛素抵抗来证实。最后，进行体内机制验证，评估 AE 对胰岛素抵抗和认知障碍的影响。
结果
转录组测序分析显示，T2DM 小鼠血清 Exos 中 MALAT1 表达降低，miR-382-3p 表达升高。MALAT1 与 miR-382-3p 之间以及 miR-382-3p 与 BDNF 之间存在靶向结合位点。体外实验表明，MALAT1 通过抑制 miR-382-3p 上调 BDNF 表达。沉默 MALAT1 或过表达 miR-382-3p 均可降低 INSR、IRS-1、IRS-2、PI3K/AKT 和 Ras/MAPK 的表达，抑制神经元增殖，促进凋亡。体内实验进一步证实，AE 可增加血清 Exos 中 MALAT1 的表达，从而竞争性抑制 miR-382-3p 并上调 BDNF 表达，改善 T2DM 小鼠的认知障碍。
结论
AE 可能通过上调血清 Exos 中 MALAT1 的表达，竞争性抑制 miR-382-3p，上调 BDNF 表达，从而改善 T2DM 小鼠的认知障碍。
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