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Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis
- Mateusz Piotr Kaczmarek
Abstract
Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed. This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001).Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects. As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.
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The top thing he found was low VEGFA as this table shows.
The paragraph explaining vegf was very interesting. My bolding:
Translational suppression of VEGF-A by circulating miRNAs implies impaired ability to adapt to hypoxia in ME/CFS patients
A sizable amount of the main findings from this analysis are consistent with experimental data in ME/CFS. Firstly, the most inhibited gene by far is VEGFA, coding for the Vascular Endothelial Growth Factor, a major secreted mediator of angiogenesis. Indeed VEGF-A levels in ME/CFS patients are decreased, as reported by Landi et al [24]. Gusnanto et al also found decreased VEGF-A as associated with ME/CFS status in a multivariate logistic regression analysis [25]. The miRNA suppression of VEGFA in ME/CFS would imply an impaired ability to adapt to hypoxia. This is of primary concern, as impaired oxygen extraction and delivery to working muscle and brain as revealed by various imaging techniques, as well as lower VO2 max seen in cardiopulmonary testing, are well-established findings in ME/CFS [26–33], and activity-dependent hypoxia caused by loss of functional sympatholysis has been proposed as a major mechanism involved in the disease pathophysiology [34]. A strong suppression of VEGF-A on the translational level can explain how such dysfunctions can persist chronically without angiogenic adaptation and how VEGF-A levels can not only be not elevated but actually measure lower than healthy controls who lack pathologic hypoxia. In addition to this canonical role in long-term angiogenic adaptations, recently a new function of VEGF-A has been established in the more immediate vasodilative regulation of bloodflow during muscle activity (exercise hyperemia). Skeletal muscle-specific deletion of VEGFA in mice resulted in decreased exercise capacity, without significant vascular changes, a picture reminiscent of ME/CFS [link]https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296060
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