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Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health

ABSTRACT: Exercise improves cardiometabolic and vascular function, though mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing (RNA-seq) in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., y-RNAs, t-RNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. Circulating ex-RNAs altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., y-RNAs) is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121874 | GEO | 2018/10/27

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.

Project description:Background/Objective: Quantitative real-time PCR (RT-qPCR) is widely used in miRNA expression studies on cancer. To compensate for the analytical variability produced by the multiple steps of the method, relative quantification of the measured miRNAs is required, which is based on normalization to endogenous reference genes. A literature search in PubMed revealed that no study has been performed so far on reference miRNAs for normalization of miRNA expression in urothelial carcinoma. The aim of this study was to identify suitable reference genes for miRNA expression studies by RT-qPCR in urothelial carcinoma. Methods: Candidate reference miRNAs were selected from 24 papillary urothelial carcinoma and normal bladder tissue samples by miRNA microarrays. The usefulness of these candidate reference miRNAs together with the commonly for normalization purposes used small nuclear RNAs RNU6B, RNU48, and Z30 were thereafter validated by RT-qPCR in 58 tissue samples and analyzed by the algorithms geNorm, NormFinder, and BestKeeper. Principal Findings: Based on the miRNA microarray data, a total of 16 miRNAs were identified as putative reference genes. After validation by RT-qPCR, miR-101, miR-125a-5p, miR-148b, miR-151-3p, miR-151-5p, miR-181a, miR-181b miR-29c, miR-324-3p, miR-424, miR-874, RNU6B, RNU48, and Z30 were used for geNorm, NormFinder, and BestKeeper analyses that gave different combinations of recommended reference genes for normalization. Conclusions: The present study provided the first systematic analysis for identifying suitable reference miRNAs for miRNA expression studies of urothelial carcinoma by RT-qPCR. Different combinations of reference genes resulted in reliable expression data for both strongly and less strongly altered miRNAs. Notably, RNU6B, which is the most frequently used reference gene for miRNA studies, gave inaccurate normalization. The combination of four (miR-125a-5p, miR-148b, miR-151-3p, and miR-151-5p) or three (miR-148b, miR-874, miR-181b) miRNA reference genes is recommended for normalization. Candidate reference miRNAs (for RT-qPCR analysis) were selected from 24 papillary urothelial carcinoma and normal bladder tissue samples by miRNA microarrays.

Project description:Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men and age-matched sedentary males at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost). Plasma exosomes were isolated, characterized, and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed using paired t-tests of baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost). Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. These results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.

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Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health

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