WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome, 2023 Hwang et al

This was a PNAS direct submission, which is almost always better than the contributed track. See here

https://scholarlykitchen.sspnet.org/2016/01/14/pnas-tighter-editorial-policy-improves-nas-papers/

 

This is very promising. From the paper , we read about the use of TUDCA, a well known inhibitor of ER Stress. According to my case, I believe that TUDCA was a key intervention towards my recovery. I just email Dr Hwang , informing him regarding the use of TUDCA and how I believe it helped me recover :





Relevant Twitter thread with the email sent to ME/CFS researchers, discussing the use of TUDCA and ER Stress amelioration : https://twitter.com/user/status/1678408083834298368

 

Any human data on salubrinal? I love the name!

 

“An EC50 of 15 micromolar is generally considered not good enough for drug development. ”

From here

https://www.alzforum.org/news/research-news/salubrinal-rescue-new-compound-fights-er-stress

 

Mind if I ask why you blurred out 6 of 10 of your regimen steps (and what is in those steps)?

 

No this is not from the intramural study team.

This was research that arose from a very tenacious lawyer from Albany with Li Fragmeni Syndrome. Its connection to the ME/CFS study was serendipitous. I really wish my article describing how it came about was published today but it'll be at least a week. August is a bad time to get stuff published. But I found it to be a really interesting story.

 

Oh god that would've been awful.

No thanks, the metabolic chamber was bad enough without having to exercise in it.

 

I haven't kept up with the federal open access policy but it used to state that NIH funded work had to be made public access within a year of publication. I hope it changes if that's still the case.

Hwang is trying to get a trial going. The paper was just published and he's been working on it...so I'd say that is pretty much immediately in research time terms.

 

As in a drug trial? Does he have some candidate compounds?

 

Fluge and Mella said they have seen ME/CFS cases who later developed cancer, and that responded to treatment of cancer.

 

This figure is the bit that really matters for sure. They have taken muscle biopsies from these 10 controls and 14 ME/CFS patients (from the intramural study i think so should be diagnosed well) and done western blots on them for WASF3, MTCO1, COX17, PERK and BiP. Here's the rest of the figure showing the western blots themselves and the quantified bar plots (just quantifying how large the blobs are from the western blot).



They see elevated WASF3, reduced ComplexIV proteins MTCO1 and COX17, increased endoplasmic reticulum (ER) stress marker PERK, and reduced protein-folding chaperone BiP. I really don't like when this type of data is represented in bar plots without showing the individual datapoints as a strip style scatter plot. We have no idea how much the groups overlap and they also don't tell us the effect size. Our only indication of variance is the error bar which as you point out represents the standard error which is the wrong metric to use - it should be standard deviation. The standard error of the mean is always smaller than the standard deviation so it looks better too. They do at least show all of the blots for all these proteins for the controls and patients (some hidden in the supplementary) so theoretically we could make these plots properly ourselves.

They go on to see the same set of proteins showing the same phenotype when they chemically induce ER stress in a separate experiment which is potentially interesting.

Their overall model for what is happening is that ER stress leads to an increase in PERK expression (a marker for ER stress), a reduction in BiP expression (an ER protein which helps proteins fold as they're being made) and in someway therefore an increase in WASF3 expression (being translated directly into the ER co-translationally I think). WASF3 translocates over to the mitochondria and binds to oxidative phosphorylation complex 3 preventing it from forming a complex with complex 4, thereby inhibiting oxidative phosphorylation activity.

According to the text S1 had all sorts of different diseases and that she had chronic fatigue and exercise intolerance - though no specific mention of ME/CFS diagnosis.

So yeah as always it needs to be replicated in a much bigger cohort with sedentary controls carefully selected and with disease controls - possible it could be a broadly applicable phenotype not specific to ME/CFS.

 

This is really interesting thankyou it sounds like you're really familiar with this technique. Agree about passage number in particular and didn't know about contact inhibition that's interesting.

Out of interest is there data showing differences in seahorse results with changes in confluence level, trypsinisation time and so on? I can see how trypsinisation could be harming the cells a little bit when you passage them but it would be a while after you trypsinise and seed the cells, let them grow, change culture medium etc before you actually carry out the assay - does it really make that much of a difference?

Also with protein quantification it seems surprising to me that differences in expression would really affect the global amount of protein in a cell so much as to make it a poor proxy for cell mass. I would have thought it would be fairly negligible or otherwise the cells would be visibly different. I'm happy to be wrong just trying to understand.

 

The steps are blurred because they are most likely steps related to me. It is very possible that specific steps are required that should be done on a personalised basis.

 

haha thankyou, it is. They're beautiful aren't they. There's also something poetic about how their land dwelling relatives might be the ugliest animals on the planet.

 

I think the 2011 analysis by Pishur et al. that highlighted the gene WASF3 in CFS, used data from the Wichita CDC study which used a very broad interpretation of the Fukuda criteria and found a prevalence above 2%.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089886/

That isn't necessarily a problem though as this study argues that WASF3 might be involved in fatiguing conditions other than ME/CFS as well.

 

Today's daily email 'newsletter' from Nature features this study as one of five 'headline storys', and links to the article in Science:

"Energy-sapping protein in chronic fatigue

A protein that disrupts cells’ energy production could be one of the reasons why people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience extreme exhaustion and cognitive problems. Researchers found higher levels of the protein WASF3 in the muscle cells of 14 people with ME/CFS than in samples from 10 healthy individuals. What exactly causes excessive levels of WASF3, which interferes with energy-generating mitochondria, remains unclear. Treatments that target the protein could help to combat related illnesses, such as long COVID."

 

There is, but it's possible it hasn't kicked in yet. There was a delay phase built into it. 2024 actually sounds about right but I'm not sure.