Aerobic exercise improves cognitive impairment in mice with type 2 diabetes by regulating the MALAT1/miR-382-3p/BDNF signaling pathway in serum-exosomes.
Aerobic exercise improves cognitive impairment in mice with type 2 diabetes by regulating the MALAT1/miR-382-3p/BDNF signaling pathway in serum-exosomes.
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DOI：
10.1186/s10020-023-00727-1
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发表时间：
2023-09-22
影响因子：
5.7
通讯作者：
Cai, Ying
中科院分区：
文献类型：
--
作者：
Wang, Mingzhu;Xie, Kangling;Zhao, Shengnan;Jia, Nan;Zong, Yujiao;Gu, Wenping;Cai, Ying
关键词：
已有文献表明，有氧运动（AE）对改善2型糖尿病（T2DM）患者的认知功能有积极作用。在此，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小鼠的认知功能障碍及其潜在的分子机制。构建T2DM小鼠模型，分离血清外显子进行全转录组测序，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的活力、增殖和凋亡能力以及胰岛素抵抗来证明。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。转录组测序分析显示，在T2DM小鼠血清exos样本中，MALAT1低表达，miR-382-3p高表达。MALAT1与miR-382-3p、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可降低INSR、IRS-1、IRS-2、PI3K/AKT、Ras/MAPK的表达，抑制神经元增殖，促进细胞凋亡。体内实验进一步证实AE可提高血清exos中MALAT1的表达，竞争性抑制miR-382-3p，上调BDNF表达，从而改善T2DM小鼠的认知功能障碍。AE可能上调血清exos中MALAT1的表达，竞争性抑制miR-382-3p，上调BDNF表达，从而改善T2DM小鼠的认知功能障碍。在线版本包含补充材料，可在10.1186/s10020-023-00727-1获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s10020-023-00727-1.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
29
作者：
Isaac R;Reis FCG;Ying W;Olefsky JM
通讯作者：
Olefsky JM
影响因子：
5.6
作者：
Barber TM;Kyrou I;Randeva HS;Weickert MO
通讯作者：
Weickert MO
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
2.9
作者：
Magnon, Valentin;Dutheil, Frederic;Tauveron, Igor;Mille, Jordan;Baker, Julien S.;Brusseau, Valentin;Silvert, Laetitia;Izaute, Marie;Vallet, Guillaume T.
通讯作者：
Vallet, Guillaume T.