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

Highlighted to me by someone else -

ME/CFS News reports on Twitter that there will be a presentation by Paul Hwang of the NIH during a symposium on molecular and cellular biology.

From the poster:

“Paul Hwang, NHLBI, National Institutes of Health, USA
ER Stress Induction of WASF3 May Underlie Chronic Fatigue Syndrome”

https://tks.keystonesymposia.org/index.cfm?e=Web.Meeting.Flyer&MeetingID=1961

 
FMMM1 said:
Highlighted to me by someone else -

ME/CFS News reports on Twitter that there will be a presentation by Paul Hwang of the NIH during a symposium on molecular and cellular biology.

From the poster:

“Paul Hwang, NHLBI, National Institutes of Health, USA
ER Stress Induction of WASF3 May Underlie Chronic Fatigue Syndrome”

https://tks.keystonesymposia.org/index.cfm?e=Web.Meeting.Flyer&MeetingID=1961

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Random thoughts -
Seems interesting since I assume a misfolded protein [is it folding?] could go unnoticed --- might explain why it wasn't identified earlier - need to know a lot of things --- prevalence --- potentially common/rare cause --- why only onset at teenage (viral?)
GWAS should pick up these things (if they're common enough)
 
mariovitali said:
So, Misfolded proteins and ER Stress @Andy @Trish @Hutan @FMMM1 . Email at a number of MECFS researchers in 2015. Add to this bile acids metabolism and choline metabolism dysregulation. 8 years



View attachment 19161
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One interesting thing once a breakthrough happens will be to establish when this could have been figured out given the level of technology and the hypotheses at the time. If only there had been some will. Or maybe a better legislative framework that doesn't allow for this negligence.

I'd be surprised if it's much later than 1990. Likely would have been harder, which would have hit the motivation factor, but probably relatively trivial by the 2000's.

Then the other question is: how many lives? How many lives did this interval destroy, simply by lack of motivation? And how much did it set back medical science? Since I'm pretty certain that a significant breakthrough will lead to huge advances all over medicine.

But that's just about figuring out the pathophysiology, which should not be needed to care for the sick, to at least respect patients enough to do something. That was always a choice.
 
Dakota15 said:
Dr. Whittemore of the NINDS said this on 2/13/23 of the ME/CFS Intramural Study (fwiw): “I just checked and they are finalizing the figures and then it will go for final internal review before being submitted. I’m told they are very close!”
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Just sharing this note from Dr. Whittemore today on the Intramural Study (not to be a nuisance). Just FYI @B_V

"I just checked and they plan to submit the paper for review within the next month. There have been many people who needed to review the paper at multiple levels at NIH which is what has taken time. They told me they would let me know when it gets submitted for review. It is hard to know how long that review will take – some journals are taking months to review submitted manuscripts, so we can’t predict how long that process will take.Thanks, and hope you are well. Best wishes, Vicky'
 
Dakota15 said:
Just sharing this note from Dr. Whittemore today on the Intramural Study (not to be a nuisance). Just FYI @B_V

"I just checked and they plan to submit the paper for review within the next month. There have been many people who needed to review the paper at multiple levels at NIH which is what has taken time. They told me they would let me know when it gets submitted for review. It is hard to know how long that review will take – some journals are taking months to review submitted manuscripts, so we can’t predict how long that process will take.Thanks, and hope you are well. Best wishes, Vicky'
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Following up from Dr. Whittemore this morning on the NIH ME/CFS Intramural Study:

"The paper has been submitted and is under review! Vicky"

Also FYI I was told by Dr. Whittemore "the journal is confidential until the paper is accepted for publication."

Tagging @B_V for visibility.
 
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Dakota15 said:
Following up from Dr. Whittemore this morning on the NIH ME/CFS Intramural Study:

"The paper has been submitted and is under review! Vicky"
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Fingers very, very crossed that something useful emerges and that the paper is published quickly

Now I'm going to make a huge leap ........

@B_V wrote
"The backstory: As part of the NIH's ME/CFS intramural study, patients had muscle biopsies. Dr. Hwang, through a somewhat seredipitous route, was looking at muscle tissue of a patient with a cancer syndrome who also had ME/CFS-like symptoms. With the tissue of this patient, he discovered a problem with this gene WASF3, and when he looked at the ME/CFS patient samples, he saw the same problem in most."

Is it just possible that the NIH funding given to study cancer fatigue reported recently has something to do with this finding linking problems with gene WASF3 in a cancer patient with ME/CFS symptoms and a group of ME patients?

No doubt it is just my wishful thinking...........
 
Binkie4 said:
Is it just possible that the NIH funding given to study cancer fatigue reported recently has something to do with this finding linking problems with gene WASF3 in a cancer patient with ME/CFS symptoms and a group of ME patients?
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Yes, that's a good thought. No idea of the answer, but it would explain something that looked very odd at the time.
 
Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies.

We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress.

Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue.

Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.

https://www.pnas.org/doi/10.1073/pnas.2302738120
 
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