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

A.L.S. Drug Relyvrio Will Be Taken Off the Market, Its Maker Says


https://www.nytimes.com/2024/04/04/health/relyvrio-als-drug.html?ugrp=m&unlocked_article_code=1.iE0.3NrH.jin8GbM2pMt6&smid=url-share

 

At the Lisbon conference on Apr 4 2024 Dr Inderjit Singh from Yale presented that they are currently devloping a leg exercise test where they can measure PCr in real time using MR spectroscopy and then see how the response differs from healthy controls.

The blue line is the outline of a leg of a person lying down, thigh to the left, and the red line with arrows is the lower leg shown lifting and lowering for exercise.

 

I have never stopped thinking about this study and I keep an eye on any new research on UPR.

I recently found this pre-print and contacted the senior author to see if he had any thoughts on me/cfs. Hwang's WASF3 paper found a disregulated pattern in the UPR proteins that you'd usually expect to both be elevated (PERK was up, but XBP1 was down) and I thought perhaps it might cross over with this finding.


[Preprint]. 2024 Dec 5:2024.11.30.626188. doi: 10.1101/2024.11.30.626188.
Dynamic modulation of IRE1α-XBP1 signaling by adenovirus
Yumi Jang, Fred Bunz

• PMID: 39677734
• PMCID: PMC11642829
• DOI: 10.1101/2024.11.30.626188

Abstract


The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1α-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1α and XBP1. IRE1α was activated in response to HAdV5 but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1α activation. The de-repression of IRE1α following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by suppressing XBP1s. Our findings highlight the defective antiviral defenses in cancer cells and further illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.

The lead author got back to me straight away and said this:

Thanks for the kind words. You bring up a interesting point. In fact, Paul Hwang and I have discussed how our results might fit in with his observations in CFS. No simple answers, but viruses could be a link.
Best,
Fred

 

I was reading the WASF3 paper again and I wondered if PCr recovery time had been measured in ME/CFS before. While the paper points to one paper (Chaudhuri and Behan 2004) that identified delayed PCr recovery in ME/CFS patients, AI identified (and I verified) 3 papers where PCr recovery in CFS patients (Fukuda criteria, no PEM required) was not significantly different from controls.

These three studies all had small sample sizes and did not require PEM. One explanation is that they lacked statistical power as a result and that is why no statistically significant difference was found. The other explanation of course is that PCr recovery time is not different in true ME/CFS patients and the 2004 paper is a statistical error.

This suggests that caution is required and these studies ought to be replicated with a larger cohort of properly diagnosed ME/CFS patients.

See below for a more detailed analysis.





McCully and Natelson (2004) (https://journals.physiology.org/doi/full/10.1152/japplphysiol.00141.2003)

The study examined 19 CFS patients meeting the Fukuda criteria (which does not require PEM) and did not find any statistically significant difference in PCr recovery time (40.6 ± 12.6 s for CFS and 40.1 ± 14.0 s for control subjects)

It could be that the null result was because n=19 and some/all of the patients did not have PEM. The test required them to pedal with high intensity for a short period and "All of the subjects performed the tests without incident". This suggests to me that the patients were very mild or did not have PEM at all.

The paper also found no significant difference in Vmax, but other papers have (e.g. this earlier paper by McCully: https://pubmed.ncbi.nlm.nih.gov/8618560/). Again this suggests the Fukuda patients in this PCr study did not (all) have true ME/CFS.

On the other hand, the paper did have some significant findings relating to blood pressure so perhaps some had true ME/CFS.

Jones et al (2010): https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02160.x

This paper examined 16 CFS patients meeting the Fukuda criteria and likewise found no significant differences in the postexercise recovery rate of PCr (CFS: 32.7 ± 9.0 s, controls: 27.2 ± 7.1 s).


Again, this paper did have some significant findings relating to muscle metabolism. It found that proton efflux was suppressed in CFS patients such that we have slower recovery in pH levels following exercise. This suggests that perhaps the Fukuda patients may have had true ME/CFS.

Wong et al (1992): https://sci-hub.ru/10.1378/chest.102.6.1716

This paper examined 22 CFS patients meeting the Fukuda criteria. Table 3 notes that PCr recovery after 1 min, 2 mins, 5 mins were all not significant. Unlike Jones et al, it diid not find any significant difference in the speed of pH recovery. It did find that acidosis occurred more quickly though.

This paper found that PCr levels reached a minimum much earlier in CFS patients than controls (i.e. they could do less exercise) but once the exercise stopped, their PCr returned to normal levels at the same speed as the controls.