Aerobic exercise improves cognitive impairment in mice with type 2 diabetes by regulating the MALAT1/miR-382-3p/BDNF signaling pathway in serum-exosomes

Molecular Medicine

Research Article

Wenping Gu¹  Shengnan Zhao²  Nan Jia²  Mingzhu Wang²  Ying Cai²  Kangling Xie²  Yujiao Zong² 

[1] National Clinical Research Center for Geriatric Disorders, Department of Neurology, Xiangya Hospital Central South University, 410008, Changsha, China;National Clinical Research Center for Geriatric Disorders, Department of Rehabilitation, Xiangya Hospital Central South University, 410008, Changsha, Hunan, China;

关键词: Aerobic exercise;    Serum-exosomes;    Non-coding RNA;    Type 2 diabetes;    Hippocampal neurons;    MALAT1;    miR-382-3p;    BDNF;   

DOI  :  10.1186/s10020-023-00727-1

 received in 2023-06-01, accepted in 2023-09-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundIt 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.MethodsT2DM 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.ResultsTranscriptome 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.ConclusionAE 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.

【 授权许可】

CC BY   
© The Feinstein Institute for Medical Research 2023

【 图 表 】

12888_2023_5172_Article_IEq25.gif

Fig. 1

13690_2023_1170_Article_IEq13.gif

Fig. 3

Fig. 4

Fig. 2

Fig. 6

Fig. 1

40249_2023_1135_Article_IEq6.gif

Fig. 2