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

Science A protein that disrupt cell's energy centers may be a culprit in chronic fatigue syndrome

quote:
“It’s extremely encouraging” to see this kind of detailed molecular approach applied to an understudied illness like ME/CFS, says Mady Hornig, a physician-scientist studying the condition at the Columbia University Mailman School of Public Health. Although the NHLBI researchers didn’t study Long Covid directly, their findings “stand to address a very common set of health issues that are very tightly tied to disability in [both] Long Covid and ME/CFS,” she says.

 

Possibly relevant, from 2011. No thread on S4ME.
New thread on this paper here:
Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data, 2011, Pihur et al
_____________

Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data
https://pubmed.ncbi.nlm.nih.gov/21584188/

We start by constructing gene-gene association networks based on about 300 genes whose expression values vary between the groups of CFS patients (plus control). Connected components (modules) from these networks are further inspected for their predictive ability for symptom severity, genotypes of two single nucleotide polymorphisms (SNP) known to be associated with symptom severity, and intensity of the ten most discriminative protein features. We use two different network construction methods and choose the common genes identified in both for added validation. Our analysis identified eleven genes which may play important roles in certain aspects of CFS or related symptoms. In particular, the gene WASF3 (aka WAVE3) possibly regulates brain cytokines involved in the mechanism of fatigue through the p38 MAPK regulatory pathway.

 

Not sure how it relates, but Prusty's study also flagged p53 as a possible factor: "Subsequent loss of miR-30 and activation of the miR-30–p53–DRP1 axis triggers a profound disruption of mitochondrial architecture.".

Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA, 2022, Prusty et al

 

Paul Hwang used this 2011 paper to ID WASF3 as a gene product of interest.

I've written an article for The Washington Post about how this research came about - it's due to the tenacity of one woman who wanted answers to her own health problems - but August is the worst time of year for science & journalism & due to some factors outside my control it won't be published until next week at the earliest.

 

The paper from Hwang et al out today shows that p53 is not involved in the pathway he identified. The patient's Li-Fraumeni Syndrome was unrelated to her chronic fatigue & related health problems.

 

I remember once having hopium that all the massive funding cancer got would some day benefit us. I mean, given the absolutely massive numbers it simply HAD to... right?

Hopefully that day has just occurred!!

 

I think of it as: DNA is the blueprint, mRNA is a photocopy of the blueprint sent to the factory floor, protein is what the photocopy tells the assembly line (ribosome) to make.

As for the paper:

"Seahorse XF Metabolic Studies.
The cells were trypsinized, resuspended in Seahorse XF DMEM assay medium (supplemented with 2 mM Glutamax, 1 mM sodium pyruvate and 25 mM glucose) (Agilent), and plated at ~5 × 104 cells/well on XF-24 well plates. The mitochondrial OCR was measured using the Agilent Seahorse XF24 Analyzer according to the manufacturer’s protocol and normalized to the protein content of each well. For measuring ex vivo muscle metabolism, the whole soleus muscle was carefully dissected and embedded on islet capture microplates and its OCR and ECAR were measured."

No description of incubation time, density at time of harvest, evaluation of spatial density in the wells once adherent, passage number. No mention of whether live and dead cells were discriminated and if differences between samples were identified during counting? How long were they trypsinised for? This info is essential for interpreting not only this kind of data in general but particularly fibroblast data because they contact-inhibit each other's metabolism and rapidly progress through senescence with each doubling. I do not agree with normalising to total protein loading when we are working in a context that assumes that protein expression is dysregulated. If your cell counting is accurate, your handling careful, and your replicates sufficient, I don't see this being necessary. It's also usually being done at the end of the assay where your different clinical groups may have responded differently to the pharmacological inhibitors and had resultant changes in protein content that do not reflect initial cell loading. And how was the protein content measured, no detail? Seahorse assays routinely cause cells to detach mostly due to the swelling effects of adding protonophores. This can lead to disruption of the originally desired cell monolayer and cells piling on top of each other which can confound particular plate-based assays (encompassing common protein assays).

For the muscle western blots that looked at WASF3 levels, where is the cohort information? Are the controls sedentary? Activity levels absolutely must be controlled for with muscle study, muscle cells change so much with activity.

There is a paucity of absolutely critical information in this paper that makes it hard for me to draw any conclusions.

 

How can this be squared with the metabolic room showing no differences from controls?

 

If they believed their own findings, they would. Instead we have this ridiculous paper with 14 ME/CFS patients and controls of no description.

 

I really hope I'm wrong but this is looking like the half assed studies that have gotten us nowhere in the past 40 years. This is why it was so important for the advocacy orgs to establish a strong narrative. If people aren't motivated they will just do the bare minimum to get their salary, throwing money at the problem isn't going to fix it (see long COVID). At least this study has an animal model and you can tell it has higher standards than the garbage we're used to (since it's coming from the NIH and their reputation is on the line) but it's still lacking that extra conviction of really wanting to figure things out. There is definitely apathy in the mix.

 

The WASF3 muscle data alone might not be that convincing, but coupled with the transgenic WASF3 mouse data showing significantly lower running distance compared to controls, plus lower OxPhos/glycosis, lower muscle glucose and higher blood lactate, it looks to me like they might be on to something.

I really hope they have already done some of the same work with the intramural study patients (the P-MRS recovery measurements and the later in vitro work).

 

Not as far as I'm aware (another missed opportunity).

 

Pretty sure there's a law that US gov't-funded publications must be open access. It is, however, under a Creative Commons license that permits noncommercial distribution, so it's legal to host a copy here despite the journal's attempt to paywall it.

 

@B_V

Thanks for keeping us all up to date. It's appreciated.

Is this the publication from Nath you alluded to last month? Will it be the main/only publication from the intramural study?