Study on the Relationship between the miRNA-centered ceRNA Regulatory Network and Fatigue, 2021, Yang et al

Abstract
In recent years, the incidence of fatigue has been increasing, and the effective prevention and treatment of fatigue has become an urgent problem. As a result, the genetic research of fatigue has become a hot spot. Transcriptome-level regulation is the key link in the gene regulatory network. The transcriptome includes messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). MRNAs are common research targets in gene expression profiling. Noncoding RNAs, including miRNAs, lncRNAs, circRNAs and so on, have been developed rapidly.

Studies have shown that miRNAs are closely related to the occurrence and development of fatigue. MiRNAs can regulate the immune inflammatory reaction in the central nervous system (CNS), regulate the transmission of nerve impulses and gene expression, regulate brain development and brain function, and participate in the occurrence and development of fatigue by regulating mitochondrial function and energy metabolism. LncRNAs can regulate dopaminergic neurons to participate in the occurrence and development of fatigue. This has certain value in the diagnosis of chronic fatigue syndrome (CFS). CircRNAs can participate in the occurrence and development of fatigue by regulating the NF-κB pathway, TNF-α and IL-1β. The ceRNA hypothesis posits that in addition to the function of miRNAs in unidirectional regulation, mRNAs, lncRNAs and circRNAs can regulate gene expression by competitive binding with miRNAs, forming a ceRNA regulatory network with miRNAs.

Therefore, we suggest that the miRNA-centered ceRNA regulatory network is closely related to fatigue. At present, there are few studies on fatigue-related ncRNA genes, and most of these limited studies are on miRNAs in ncRNAs.

However, there are a few studies on the relationship between lncRNAs, cirRNAs and fatigue. Less research is available on the pathogenesis of fatigue based on the ceRNA regulatory network.

Therefore, exploring the complex mechanism of fatigue based on the ceRNA regulatory network is of great significance.

In this review, we summarize the relationship between miRNAs, lncRNAs and circRNAs in ncRNAs and fatigue, and focus on exploring the regulatory role of the miRNA-centered ceRNA regulatory network in the occurrence and development of fatigue, in order to gain a comprehensive, in-depth and new understanding of the essence of the fatigue gene regulatory network.

Open access, https://link.springer.com/article/10.1007/s12031-021-01845-3

 

I understand very little of the abstract, but that snippet looks very salient. If energy regulation is faulty then presumably energy delivery can be compromised. And from that presumably an energy shortfall provokes fatigue, as nature's way of ensuring people do not then try to draw on energy that is not available to use.

 

The paper supports my hypotheses for ME. For quite a long part of my ME, T2 (3-5 diiodothyronine) was an important treatment for me. A single dose would block an otherwise worsening of my symptoms for a very consistent 21 days. Hampering thyroid function, and thus T2 levels, would make my symptoms worse. T2 plays a role in miRNA transcription. I assume the boost in T2 boosted (or maybe blocked) production of something with a consistent lifespan of 21 days.

No, I've only skimmed the paper, but the gist of it seems to be that the various RNA modulators affect neural function, which results in central fatigue. They also affect the immune system and mitochondrial function, which are other pathways to what we perceive as fatigue. This paper shows that it's quite reasonable for some PWME to have reduced ATP production in their muscles, but other PWME do not, yet still experience 'fatigue' due to the neurological dysfunction. As someone in the latter subset, I appreciate the confirmation. Fixing ATP production in muscles of people who have that ME symptom might not treat the other ME symptoms: your muscles might be up to the task of a long bike ride, but you'd still wake up feeling unrefreshed, and you'd still feel 'fatigued' all day.

Now, does this lead to a treatment real soon now?

 

Has it? Compared to what? Based on what definition or degree? How would we even know when no one's counting and we don't know how to count and we don't even know what fatigue is or have a definition for it and many many other problems?

I mean maybe it has but literally no one has counted that so it seems like a very speculative assertion. The things that pass peer review...

 

While I encourage novel hypotheses, I don't find the hypotheses terribly compelling given the current evidence. I'd encourage the authors to conduct in-depth empirical studies if they are serious about the hypothesis.

Unfortunately, in the narrative review, the authors haven't clearly distinguished the types of fatigue (they don't seem to understand the function of central fatigue, for example) and contributing processes in different types of tissues, so everything is a bit non-specific. I will note that The 'NF-κB pathway, TNF-α and IL-1β' themselves aren't a direct cause or contributor to fatigue.

That said, ncRNAs may well be involved, but I doubt they alone form the central feedback loops that lead to persistent fatigue.

 

Reminds me of this study:
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The expression signature of very long non-coding RNA inmyalgic encephalomyelitis/chronic fatigue syndrome
Chin‑An Yang1,2,3,4 , Sandra Bauer5, Yu‑Chen Ho3, Franziska Sotzny5, Jan‑Gowth Chang1,3,4† and Carmen Scheibenbogen5