Abstract
Microgravity impacts various aspects of human health. Yet the mechanisms of spaceflight-induced health problems are not elucidated. Here, we mapped the fusion systemic analysis of the serum metabolome and the circulating microRNAome in a hindlimb unloading rat model to simulate microgravity. The response of serum metabolites and microRNAs to simulated microgravity was striking. Integrated pathway analysis of altered serum metabolites and target genes of the significantly altered circulating miRNAs with Integrated Molecular Pathway-Level Analysis (IMPaLA) software was mainly suggestive of modulation of neurofunctional signaling pathways. Particularly, we revealed significantly increased miR-383-5p and decreased aquaporin 4 (AQP4) in the hippocampus. Using rabies virus glycoprotein–modified exosomes, delivery of miR-383-5p inhibited the expression of AQP4 not only in rat C6 glioma cells in vitro but also in the hippocampus in vivo. Using bioinformatics to map the crosstalk between the circulating metabolome and miRNAome could offer opportunities to understand complex biological systems under microgravity. Our present results suggested that the change of miR-383-5p level and its regulation of target gene AQP4 was one of the potential molecular mechanisms of microgravity-induced cognitive impairment in the hippocampus.
Highlights
MATERIALS AND METHODSSpaceflight impacts various aspects of the space travelers’ health, known as space adaptation syndrome, including bone loss, skeletal muscle atrophy, cardiovascular dysfunction, immune system dysregulation, and alterations in circadian rhythms and cognitive functions (Manzey and Lorenz, 1998; Grimm et al, 2016; Rea et al, 2016)
Food intakes of the HU28 rats were not affected by hindlimb unloading which is consistent with the results previously reported (Feng et al, 2016)
Micro-computed tomography (MicroCT) results showed that the rats had significant osteoporosis after 28 days of hindlimb unloading and indicates that the HU model could be used to simulate the space microgravity (Chen et al, 2016)
Summary
Spaceflight impacts various aspects of the space travelers’ health, known as space adaptation syndrome, including bone loss, skeletal muscle atrophy, cardiovascular dysfunction, immune system dysregulation, and alterations in circadian rhythms and cognitive functions (Manzey and Lorenz, 1998; Grimm et al, 2016; Rea et al, 2016). We first profiled and integrated the serum metabolome and miRNAome from rats undergoing simulated microgravity using hindlimb unloading (HU) method, aiming to probe the composition of serum metabolites and circulating microRNAs. Through multi-omics analysis, several differently regulated miRNAs found in serum were the master regulators mediating microgravity-induced effects in other tissues, especially miR-383-5p and its target gene water channel aquaporin 4 (AQP4) in hippocampus. Multi-omics methods can help us to detect changes through systematically understanding gene and/or protein expression and molecular networks in various tissues, and unravel the mechanisms behind microgravityinduced problems and find effective countermeasures to spaceflight-induced alterations. Total RNA was extracted from rat hippocampus and glioma cell using standard Trizol-based protocols according to the manufacturer’s instructions. P value < 0.05 was considered as statistically significant difference (∗p < 0.05, ∗∗p < 0.01)
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