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

Mingzhu Wang; Kangling Xie; Shengnan Zhao; Nan Jia; Yujiao Zong; Wenping Gu; Ying Cai

doi:10.1186/s10020-023-00727-1

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

Mol Med. 2023 Sep 22;29(1):130. doi: 10.1186/s10020-023-00727-1.

Authors

Mingzhu Wang^#¹, Kangling Xie^#¹, Shengnan Zhao¹, Nan Jia¹, Yujiao Zong¹, Wenping Gu², Ying Cai³

Affiliations

¹ National Clinical Research Center for Geriatric Disorders, Department of Rehabilitation, Xiangya Hospital Central South University, Changsha, 410008, Hunan, China.
² National Clinical Research Center for Geriatric Disorders, Department of Neurology, Xiangya Hospital Central South University, Changsha, 410008, China.
³ National Clinical Research Center for Geriatric Disorders, Department of Rehabilitation, Xiangya Hospital Central South University, Changsha, 410008, Hunan, China. 403991@csu.edu.cn.

^# Contributed equally.

Abstract

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain-Derived Neurotrophic Factor / genetics
Cognitive Dysfunction* / genetics
Cognitive Dysfunction* / therapy
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / genetics
Exosomes*
Insulin Resistance* / genetics
Mice
MicroRNAs* / genetics
Phosphatidylinositol 3-Kinases
RNA, Long Noncoding* / genetics
Signal Transduction

Substances

Brain-Derived Neurotrophic Factor
microRNA 382, mouse
MicroRNAs
Phosphatidylinositol 3-Kinases
RNA, Long Noncoding
Bdnf protein, mouse
Malat1 long non-coding RNA, mouse