Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in ME/CFS, 2020, Narayan et al

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703497/

 

Interesting. Curious if those reduced differ from for example the Moreau study.

 

Fukuda criteria.

Also, 60% of those who exercised where female, while those who didn't were 80% female. Exercise cohort, 27% were diagnosed with fibromyalgia, non-exercise 40%. And there were three times more in the non-exercise than in the exercise group. While there might be challenges to do so, surely it would be best to match the cohorts more closely?

 

I'm not sure that the flaws in the study matter. I get the impression that even really well done studies that find something really significant ... simply won't be followed up on.

 

I'm confused about the cohort here. Is it a subgroup from a larger (GWI&CFS&HCs?) study doing double duty? Or a different cohort but they're using data from the larger study as a sort of control?

Does the "suggested upregulation of phosphoinositol signaling pathways" (in the conclusion) tie in in any way with the Griffith TRPM findings?

I don't understand this at all but I googled 'phosphoinositol signaling' and stumbled across papers describing its interaction with TRPM receptors, hence my question.

 

This is very interesting. Very much tickling my confirmation bias right now!!

One of my pet hypotheses is infection induced dysregulation of cellular adhesions (in specific tissues), involving integrins and the https://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway

Some similar pathways were found (albeit in a quite different study) here:
https://www.s4me.info/threads/ident...od-biomarkers-me-cfs-2019-eguchi-et-al.12424/

The authors of the current study note:

So the findings in part could simply reflect the presence of exosomes...

Semaphorin 4G itself is involved in axonal growth cones and regulating cellular adhesions, binding through Plexin-B2, which itself complexes with neuropilins and integrins... Activation of Plexin B2 can lead to activation of the AKT pathway leading to MTOR activation...

Also, another coincidence: the suggestion that miR-608 downregulates COL5A1, when that is the gene for which several SNPs cause variants of Ehlers-Danlos Syndrome.

Unfortunately my enthusiasm is a little tempered by the poor experiment vs control group matching as pointed out by Andy.

 

Can you explain what role cellular adhesion play in the body and what kind of illness would result from its disturbance?

Does it has anything to do with the endothelium?

 

Cellular adhesions are fundamental to all multicellular organisms. From proper structural formation of tissues (cell-cell and cell-extracellular matrix structures), to signalling between adjacent cells and the extracellular matrix, to vesicle trafficking, nerve/neuron connectivity, a range of immune cell functions (including migration along the endothelium) and invasion of cells by viruses and other microorganisms. And yes this list includes endothelial permeability, mechanical sensing (such as endothelial shear stress) and flow mediated dilation.

Since this aspect of biochemistry plays such a variety of functions, the overall regulation can be complex and a variety of diseases can result.

It goes without saying that any such hypotheses have to be quite specific to be useful. My hypotheses are not yet terribly convincing. But my initial approach was different - namely, looking at all of the infectious cause of ME and looking at what they had in common, what cellular dysregulation they could induce (in the peripheral vascular endothelium for example). I also look at what I consider to be the key physiological finding in ME so far (the gas exchange threshold on the 2nd consecutive CPET) and given what we know about neurology and physiology (and what has already been ruled out as not causing ME) a short list of causes. Additional nice-to-haves are matching biochemistry kinetics patterns to symptom patterns over time, and potentially initial onset kinetics (including relapse-remitting patterns).

 

Would cellular adhesion abnormalities influence gut and brain barrier permeability? There was this study which found an increase of gut bacterial translocation following exercise in ME/CFS.

 

Yes.

"Integrin–Matrix Interactions in the Cerebral Microvasculature"
https://www.ahajournals.org/doi/10.1161/01.ATV.0000232525.65682.a2

More on this, the scientific rationale for use of Natalizumab in MS, a α4-integrin inhibitor is to reduce immune cell trafficking across the blood-brain barrier.

 

Does it make physiological sense to try and explain PEM as an inflammatory reaction of the brain, resulting from translocation of things into the brain that shouldn't be there, in turn resulting from problems with the blood-brain barrier?

 

That sounds more like the hypothesis behind MS...

 

Is there anything which should jump out in a GWAS study (or anything which has turned up in a GWAS study) which would support this hypothesis?
EDIT - @Simon M - a GWAS study might give us clues here i.e. to see if there is indeed a basis for this hypothesis.

Was the "key physiological finding in ME so far (the gas exchange threshold on the 2nd consecutive CPET)" based on a study which had controls with similar (very low) activity levels i.e. is it unique to ME?

 

I recall an earlier paper by Baraniuk which suggested leaky blood brain barrier - I think Baraniuk took out a patient related to that. Still interesting though - if there's evidence.

Is there a gut brain thing?

 

I don't know if it's been posted in this thread already, but Baraniuk published a paper not completely unrelated about 3 years ago,

Exercise-induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects, 2017, Baraniuk. Here is the S4ME discussion on it.

I'm trying to follow the cohort process. First, funding came from a variety of sources and the same paragraph in this paper attributing funding can be found in several papers on GWI or ME/CFS from the past 2 years.

eg. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220213/

Second, it's hard to tell if it's all data on a couple of cohorts from 3-4 years ago. That paragraph you posted is unintelligable to me, to be frank, I think the author's should try to make that stuff more clear. Could be me, of course. The original NIH study was for an fMRI study in 2016. I checked Spotila's funding wrap-up blogs and it didn't look like he had been funded for an ME/CFS study since than, and I didn't see Naryan either. Again, could be me missing something.

Full disclosure, I haven't read this paper yet, I was just checking the circumstances around it out of curiousity from your post.

 

Risk factors, but not causative factors. I suspect there will be EDS related findings in the GWAS study.

Yes, I'm talking about the reduction in performance at in the ventilatory threshold, a phenomena that has not been observed in other chronic illnesses such as MS as well as sedentary controls. The key point about performance at the ventilatory threshold is it is the key measurement that is not affected by motivation - reduction in VO2Peak and related measurements can simply result from participants ceasing the test early.

Everything in biology is tied in together in some way. I am curious as to what papers you saw.

The question is there a clear/direct connection to TRPM3 that the Griffith group is interested in and the answer is no, there was no miRNAs associated with TRPM3.

TRPM7 does play a role in endothelial cellular adhesions and there is a connection between AKT/PI3K pathways and calcium flux.

 

Thanks @Snow Leopard interesting i.e. "ventilatory threshold is it is the key measurement that is not affected by motivation" - I assume that there are issues with selecting participants (in studies) on this basis!

@Michiel Tack

 

I don't quite understand what you mean. If someone is willing to participate in a CPET study, they are going to put in a strong effort, but this is not the same as a true maximal (VO2) effort. It is difficult to put in a true maximal effort if you are not accustomed to exercise and doubly so when you have ME and your body is screaming at you to stop.

There are inconsistencies within and across studies for motivation during CPET tests, such as the strategies employed by those supervising the test to continue, along with personal motivation - from personal experience, it was hard to know when you are supposed to stop, I continued for several minutes after it got very hard and it felt like my heart was about to explode out of my chest (CPET tests are known to induce high blood pressure and high heart rates that I was not accustomed to). It wasn't until I started to feel dizzy that I knew for sure that I had reached a true VO2Max. If I stopped several minutes earlier, I still would have met criteria for "maximal effort" (RER>1.1, temporary VO2 Plateau), but this would not have been a true maximum.

 

I wasn't sure if this was a realistic option to select participants for a ME study i.e. maximal (VO2). E.g. Cara Tomas, and others, published a study recently (small number of participants) and it would be interesting to see that replicated in a larger study. However, selecting participants on the basis of maximal (VO2) might not make it through the ethics committee!