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

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.

Demethylation of miR-299-5p by aerobic exercise relieves insulin resistance in the vascular endothelium by repressing resistin.

AIMS: Insulin resistance (IR) is a critical marker underlying type 2 diabetes mellitus (T2DM). Exercise is reported to prevent IR, yet the mechanism of which is complicated and largely unknown. Here, the study aimed to ascertain whether and how aerobic exercise mediates IR in T2DM. METHODS: An in vivo model of high-fat diet (HFD)-induced IR and an in vitro model of high-glucose-induced IR were constructed. RESULTS: Aerobic exercise training in mice led to attenuation of IR in the vascular endothelium. microRNA-299-5p (miR-299-5p) expression was deficient in T2MD, which could be restored by aerobic exercise through modulating the DNA methylation modification enzymes. The expression of miR-299-5p enhanced by aerobic exercise consequently resulted in ameliorating the IR in vivo. Furthermore, increased levels of nitric oxide (NO), reduced levels of Angiotensin II (Ang II), vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in response to miR-299-5p elevation suggested the anti-IR role of miR-299-5p in IR-cell model. Dual-luciferase reporter and ChIP assays identified that miR-299-5p could bind to resistin and hence repressed the resistin level. CONCLUSION: The key observation of the study is that aerobic exercise stimulates miR-299-5p-targeted resistin inhibition through demethylation, which underlies the mechanism of reducing IR.