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Transcriptomic Responses to Neuromuscular Electrical Stimulation (NMES) in Muscle, Brain and Plasma Exosomes in WT and Klotho Deficient Mice [ncRNA]

ABSTRACT: Previous studies indicate extracellular vesicles (EVs) play a role in cellular communication which may be impacted by neuromuscular electrical stimulation (NMES), a noninvasive approach to improve daily living and functional motor activities. Therefore, we utilized NMES to stimulate the tibialis anterior of WT and KlHET mice and evaluated transcriptomic profiles of muscle tissue, brain tissue, and plasma-derived EVs. Muscle mRNA indicate that genes related to metabolic processes are upregulated in response to NMES in but have little overlap in WT and KlHET NMES versus control. Brain mRNA in WT shows upregulation of several genes related to blood flow and cell adhesion processes while KlHET shows downregulation in cell adhesion processes and immune function. In plasma-derived EVs, little overlap in ncRNA, with the exception of let-7d-5p which regulates insulin signaling targets and immune responses, was present. Findings indicate local and distal transcriptomic metabolic effects of NMES are mediated by KLOTHO deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE296704 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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Transcriptomic Responses to Neuromuscular Electrical Stimulation (NMES) in Muscle, Brain and Plasma Exosomes in WT and Klotho Deficient Mice [ncRNA]

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