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

[Andy]

Personally I would rate myself as both lacking in stamina and in relative strength.

 

[Dakota15]

Oh yes, it is slated to run after Labor Day now ..so should be next week. I should have learned not to anticipate publication dates by now, haha.

Not trying to be nosy @B_V, I just wanted to make sure I didn't miss it! All the best.

 

[Robert 1973]

Just started trying to make my way through the paper (thanks @B_V).

One thing jumps out at me. Hwang et al write:

“WASF3 Tg soleus muscle, with confirmed reciprocal changes in WASF3 and MTCO1/2 levels (SI Appendix, Fig. S7A), showed significantly lower OCR to ECAR ratio as an index of oxidative metabolism compared with that of wild-type mice, indicating increased WASF3 reprograms its metabolism toward glycolysis (Fig. 2 E, Left). In support of this, the WASF3 Tg mice showed higher blood lactate levels compared with that of wild-type mice, reflecting the finding of elevated blood lactate in ME/CFS patients at rest, which correlated with their postexertional malaise severity”.

The reference they give is: 21. A. Ghali et al., Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome. Sci. Rep. 9, 18817 (2019).

My understanding is that other studies have shown no evidence of increased blood lactate in ME/CFS patients – only some evidence of delayed lactate clearance after exercise. Am I mistaken?

 

[Robert 1973]

Chronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance. Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.

Interesting to note that Metformin is reported to suppress ER stress. See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826674/#

From the link above:

“Previous studies indicated that metformin suppresses the ER stress through the 5’ adenosine monophosphate-activated protein kinase (AMPK)-phosphatidylinositol 3 kinase (PI3K)-c-Jun NH2 pathway [18]. It is also possible that it reduces the level of reactive oxygen species and DNA damage induced by ER stress [22].”


Thread on paper which suggests Metformin may reduce chances of developing Long Covid: https://www.s4me.info/threads/outpa...ment-of-long-covid-2023-bramante-et-al.31101/]

 

[Jaybee00]

Merged thread

She wrote to a scientist about her fatigue. It inspired a breakthrough. Brian Vastag

https://wapo.st/3Pem0G4

Her dogged efforts lead to a new scientific discovery that may help others with long covid and other chronically fatiguing illnesses

 

[Jaybee00]

A lot of positive comments so far e.g.

“This is a really interesting and well done article on an important topic. Chronic fatigue without and obvious cause (eg. Hypothyroidism) is fairly common, and hard to evaluate. It is unfortunately easy to blow off the complaints, or consider them psychogenic. Since there isn’t a clear treatment, it doesn’t medically harm the patient, but psychologically it is harmful. In addition, it is very hard for these patients to get disability as there is no test to prove disease. If this explains even a fraction of the cases, and provides a molecular mechanism, it is a big step forward.

It shows the power of government funded basic science research. To recall, under trump, and with the Republican controlled house, there have consistently been efforts to dramatically reduce funding to NIH. This should be strongly opposed, given the huge benefits we have received from basic science research to date, and can expect to receive going forward.”

 

[B_V]

My article about Amanda Twinam, the woman whose doggedness in understanding her own health problems led to Paul Hwang's work, is finally out. Also in print in the Tuesday Health & Science section.

https://www.washingtonpost.com/health/2023/09/17/fatigue-cfs-longcovid-mitochondria/

 

[Trish]

As a non subscriber, I can't read your article, @B_V. Is there any way we can access it?

 

[B_V]

As a non subscriber, I can't read your article, @B_V. Is there any way we can access it?

Yes, here is a gift link:
https://wapo.st/3Pem0G4

 

[Hoopoe]

Stunning comment by the lead researcher

Hwang began a detailed biochemical search. He found that skin cells taken from Twinam appeared to be churning out an excess of a protein called WASF3. Zooming inside Twinam’s mitochondria, Hwang and colleagues eventually saw something stunning: Like a stick jammed into bicycle spokes, the overabundant protein was literally gumming up the gears of energy production.

The protein Twinam made too much of? It rudely jams up the supercomplex. “It’s making this whole thing disassemble,” Hwang says. “It’s literally falling apart.”

 

[Trish]

Yes, here is a gift link:
https://wapo.st/3Pem0G4

Thanks, Brian, that's an excellent article.
Do you know whether more research on this in more people with ME/CFS is planned?

 

[B_V]

Thanks, Brian, that's an excellent article.
Do you know whether more research on this in more people with ME/CFS is planned?

Paul Hwang is trying to get a clinical trial of Relyvrio going. It's an ALS drug and he has some evidence it can reduce overexpressed WASF3.

 

[Kitty]

Paul Hwang is trying to get a clinical trial of Relyvrio going. It's an ALS drug and he has some evidence it can reduce overexpressed WASF3.

That sounds promising. It's the sort of thing a pharmaceutical company might be interested in when they've got a very expensive drug but a rather limited potential market. If it turns out there is a reasonable case to be made for a trial, it would be in their interests to get behind it.

 

[Jaybee00]

Good article! @B_V

1) How to get tested for this outside of NIH (WASF3 over expression)?

2) Based on this small sample a significant percentage (35%) don’t have this issue but still are definitively diagnosed with MECFS—so maybe the non-WASF3 is a subset?

Slightly off-topic
3) Do you know if she received cyclophosphamide as part of her chemotherapy—and did she notice any improvement in her fatigue level with cyclophosphamide treatment?

 

[josepdelafuente]

Great article @B_V !

And yes as @Jaybee00 mentions, I'm wondering if this might be something any of us could get tested for (WASF3 over expression), e.g outside the U.S

 

[Hoopoe]

Would it be possible to measure WASF3 expression in a muscle biopsy that was stored in a freezer for at least a year?

What would be required and what would it cost? I could approach the doctor that did the biopsy and ask but would like to have some idea of whether I'm making a very costly and time consuming request or not.

 

[Sid]

As for Twinam, after decades of feeling ill with no diagnosis that ever made sense, she believes her own story has finally been legitimized, and in a major scientific journal at that.

“There’s this difference between cancer and chronic fatigue syndrome,” a diagnosis her rheumatologist has finally added to her file, she says. “Everybody believes you when you have cancer. You joke about having a ‘cancer card’ to get off from doing things. No one is handing out CFS cards. I can finally say, ‘It’s not psychological. I’m not a malingerer.’ We now have a scientific explanation.”

So true.

 

[Jaybee00]

Another article comment:

“At the end of this article, I burst into tears.In the 40 years I've been battling this, there as never been such activity as this. No promising anything in terms of research. I'm especially hopeful for treatment as my youngest child is now also suffering with CFS. I don't want him surfing the next 40 years as I have.If I could hug Twinam right now, I would!”

 

[Mij]

From the article:

"The red flags that Twinam had an unrecognized chronic illness began after her suspected case of mono in high school. She says she feels she never fully recovered. One big tell: In college, after exercising, Twinam would not experience an endorphin rush.. Instead, she told her friends she “felt like garbage.”

Exactly what I experienced during sudden viral onset PVFS in 1992. I didn't feel like 'garbage', I felt very flat, no PEM just flat.

 

[Robert 1973]

Yes, here is a gift link:
https://wapo.st/3Pem0G4

Thanks, Brian. Really good article and fascinating story.

Can we share the gift link on social media?

Love this line: “For Hwang, developing a treatment for the illness is now ‘what keeps me going.’”

Hope is what keeps me going. And Hwang has given me another much needed hit.


Also, interesting to note that the article states: “Twinam undertook a years-long journey to understand her continuing fatigue, neuropathy, muscle weakness and other problems.”

This contrasts with Hwang’s finding that Tg mice with extra WASF3 had no significant reduction muscle strength – only reduced ability to exercise:

“To better understand the role of WASF3, the team engineered mice to produce excess WASF3. They found that, similar to people with post-exertional malaise, muscles in these mice were slow to recover after exercise. The mice also showed a 50% reduction in their ability to run on a treadmill, even though their muscle strength was comparable to mice without extra WASF3.”