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Silencing of exercise induced microRNA-501, microRNA-409 leads to aberrant neuronal homeostasis

ABSTRACT: Exercise has been shown to boost cognition in mammals. However, the underlying mechanism remain poorly understood. We hypothesized that circulating microRNAs may correlate to improved cognitive functions, particularly cognitive flexibility after exercise and could be critical for neurons functions. To address this, in our study, healthy human volunteers participated in an exercise paradigm coupled with various cognitive tests performed prior to and after exercise and high quality small RNAome data were generated from total blood collected at two time points (pre- and post-exercise). Advanced comparative computational approaches were employed to select candidate microRNAs and multiple functional experiments were designed to test effect of those candidates on neuronal transcriptome, and neuronal functions. Our analyses revealed a cluster of circulating microRNAs related to improved cognitive flexibility. After rigorous analyses, we selected two candidate microRNAs and inhibition of these microRNAs led to up-regulation of genes, conserved in increased stress responses and downregulation of genes related to synaptic morphology and functions. Functional data revealed that the two microRNAs are indeed critical for maintenance of neuronal functions and morphology. Newly discovered cluster of microRNAs shed light on the mechanism of exercise-improved cognition and the two candidate microRNAs are potential RNA therapeutic target against dementia.

ORGANISM(S): Mus musculus

PROVIDER: GSE171633 | GEO | 2022/04/07

REPOSITORIES: GEO

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Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.

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Silencing of exercise induced microRNA-501, microRNA-409 leads to aberrant neuronal homeostasis

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