[EV] proteomics uncovers energy metabolism, complement system, and [ER] stress response dysregulation postexercise in males with [ME/CFS], 2025,Glass+

[hotblack]

Genecards links for easy perusal, sorry I lost the nice colour coding and not all have directly associated genes, I haven’t checked them all individually yet, just generated the URLs

Spoiler: Genecard links

Baseline
Lower:
ANXA3
VIM
RAP1A
PRKAR2A
SCRN1
PCSK6
PPP1R14A
SYNCRIP
DARS1
MPST
DAPP1
PAFAH1B1
PGD
TXNDC5
FKBP3
ADH5
HNRNPK
RDX
KPNB1
CMPK1
RAB7A
AKR1A1
CNPY2
PTGES3
PSMA5

Higher:
BLMH
TBCA
GGCT
NSF
CD84
ACTN3

15 mins after exercise
Lower:
DSG1
RAP1A
SERPIN89
PRKAR2A
SCP2
GAB
DARS1
TXNDC5
PTPN11
ADH5
PDCD6IP
CRLF3
HNRNPK
TAOK3
GSTP1
PGK1
ERP44
P1L4 (no genecard, see RPL4, thanks @Hutan)
IPO07 (no genecard, possibly IPO7 ?)
VBP1
FKBP3
UBE2L3
PSMA4
USO1
INPP4B
P4HB
YWHAE
CLTA
HYOU1
TPM3
PDIA4
RDX
RAB8B
PTGES3
CALR

Higher:
BLMH
PRDX6
ADD1
TFRC

24 hours after exercise
Lower:
VIM
SYNCRIP
PRKAR2A
ANXA3
ARCN1
DARS1
VBP1
TPT1

Higher:
GGCT

 

[Hutan]

IPO07 (no genecard, possibly IPO7 ?)

Sorry, that was my error. Yes, IPO7

 

[Hutan]

P1L4 (no genecard)

"The P1L4 gene is a ribosomal protein L4 (RPL4) gene. It is part of the ribosomal protein L4 family, which is involved in the process of translation in all living organisms. RPL4 is a structural component of the ribosome, playing a crucial role in protein synthesis."

RPL4 with gene card link

 

[poetinsf]

I haven't read the paper yet, but it seems like yet another discovery of anomaly rather than anything groundbreaking.

1) Despite anecdotal reports of immediate PEM, PEM is usually defined as worsening of symptoms after 12-48 hours. For some, PEM is like a truck rolling over you on precise schedule. If the anomaly was widely observed after 15 min, it may not be related to PEM. It could be related more to rapid fatiguability of sick people instead.

2) As usual, there is no causality. I'm not sure if it is any more significant than VO2 or VT anomaly that they say it was correlated to except that it is an observation at cellular level.

 

[jnmaciuch]

If the anomaly was widely observed after 15 min, it may not be related to PEM. It could be related more to rapid fatiguability of sick people instead.

I don’t think they are claiming that the 15 minute time point is PEM itself. Rather, it would be an indication of a more immediate response to exertion which may trigger whatever mediates PEM at a later timepoint.

Which is exactly what we’d expect with a hypothesis that PEM is an immune-mediated response to activity—an immediate start of some cascade during or right after activity, with a different manifestation at a later time point corresponding to the known delay of immune reactions.

 

[hotblack]

"The P1L4 gene is a ribosomal protein L4 (RPL4) gene. It is part of the ribosomal protein L4 family, which is involved in the process of translation in all living organisms. RPL4 is a structural component of the ribosome, playing a crucial role in protein synthesis."

RPL4 with gene card link

Thank you! Where did you find that? I couldn’t find anything clear and went around in circles.

 

[mariovitali]

Some comments regarding this study. It mentions ER Stress and protein folding as potentially important. I would also like to point to your attention the mention on PDIs (Protein Disulfide Isomerase).

For readers who are aware of my work, ER Stress, Protein folding and Autophagy was one of the first medical concepts being identified using machine learning and network analysis methods. Regarding PDI mentioned in the paper, disulfide bonds are closely related and these have been also identified previously (I am not linking a relevant Twitter post as some may not be able to access it).

I used a number of reasoning engines where I submitted the following question : "Patients of an unknown syndrome were found to have the following genes differentiated Pre and Post-exercise . Suggest potential causes : " and then I pasted the downregulated/upregulated genes. Note that I did not mention Post Exertional Malaise, Fatigue or any other symptom. Here is a snapshot from the session by Google Gemini 2.5 :




The session can be found here : https://g.co/gemini/share/619a56d67061

EDIT : We should point our attention to the different ways in which Glutathione production might get impaired (my hypothesis)

 

[forestglip]

I used a number of reasoning engines where I submitted the following question : "Patients of an unknown syndrome were found to have the following genes differentiated Pre and Post-exercise . Suggest potential causes : " and then I pasted the downregulated/upregulated genes. Note that I did not mention Post Exertional Malaise, Fatigue or any other symptom. Here is a snapshot from the session by Google Gemini 2.5 :

That's kind of surprising. Are you sure you don't have any kind of custom instructions referring to ME/CFS that could influence it to answer in this way?

 

[mariovitali]

That's kind of surprising. Are you sure you don't have any kind of custom instructions referring to ME/CFS that could influence it to answer in this way?

I agree but I didn't provide any information. The session was totally new. I am very much inclined to submit findings of another study with proteomic results using the same prompt and see what i get. I believe that a word which may have biased results is "exercise"

 

[Yann04]

I guess the simple fact that studying proteins pre and post exercise seems something that would be done more in ME/CFS will bias the model.

But that’s impressive nontheless @mariovitali that it directly said PEM

 

[wigglethemouse]

Here is a snapshot from the session by Google Gemini 2.5 :

What really stood out to me in the full text of the link you provided is that it is now certain that exercise brings about changes that are different from muggles and not good.

It also made me realise again what a quality research team this is - one of the few that has insisted on exercise challenges and uses what seem like robust protocols e.g. use of sedentary controls.

I know Systrom has identified clear biological differences with exercise but who else has done deep biological dives with exercise? Moreau in Montreal, but that is just an arm exercise, and I'm not clear what group differences he found - most seemed to be sub-typing by symptoms and then looking at micro RNA expression. I wish there were lots and lots more. Hopefully the good day, bad day, studies will show something along the same lines. We also have the Systrom biological effects deep dive on muscle in progress.

 

[Hutan]

On P1L4:

Thank you! Where did you find that? I couldn’t find anything clear and went around in circles.

I've just gone round in circles myself.

I'm sorry. AI also said in my search yesterday:

The P1L4 gene, also known as RPL4, is a gene that encodes the ribosomal protein L4. This protein is a structural component of the ribosome, a large molecular complex responsible for protein synthesis.

And, it is still insisting it is right:
[QUOTE="AI"The statement that the P1L4 gene is a ribosomal protein L4 (RPL4) gene, part of the ribosomal protein L4 family, and involved in protein synthesis is accurate.[/QUOTE]
But, it doesn't seem to have any basis to do that. I did not think AI could get something so basic wrong. Clearly, nothing it says can be trusted.

Maybe someone who knows the authors could ask them about that gene name?

 

[forestglip]

I'm sorry. AI also said in my search yesterday:

The search engine AIs are very bad with hallucinations, much worse than the stand-alone chatbots. I wouldn't ever trust the Google Search AI without checking its sources. I mean that's good practice with any AI, but I feel like with the search AIs it's basically a coin flip whether it just makes something up.

Edit: I sent them an email. But I'm guessing P1L4 is supposed to be NAP1L4, a protein listed in supp. table 2.

 

[SNT Gatchaman]

The AI might still be right. To my non-expert look, RPLP1L4 still sounds like it might be the best match for "P1L4" though it was withdrawn from GeneNames.org

RPLP1 listing here and GeneCards

 

[poetinsf]

I don’t think they are claiming that the 15 minute time point is PEM itself. Rather, it would be an indication of a more immediate response to exertion which may trigger whatever mediates PEM at a later timepoint.

I'd file that under "anything is possible" without knowing what that trigger is and how the reported EV anomaly pulls that trigger down the road. That's a longer chain of events, therefore a bigger speculation, than the anomaly being the trigger itself.

Which is exactly what we’d expect with a hypothesis that PEM is an immune-mediated response to activity—an immediate start of some cascade during or right after activity, with a different manifestation at a later time point corresponding to the known delay of immune reactions.

We already know that the immune response to exercise is delayed. The question is: how does EV anomaly that they found cascades to PEM? The claim that "these findings provide insight into the molecular basis of PEM and suggest promising targets for improving recovery and energy metabolism in ME/CFS." is pretty unwarranted if you ask me.

 

[mariovitali]

So I did a second run using my favorite method which is submitting the same input to a number of reasoning AI engines. This time the prompt was even more generalised.

Prompt :

Patients of an unknown syndrome were found to have the following genes differentiated at different time segments. Suggest a potential cause and possible associated symptoms . At baseline ,the following were found to be Lower expressed : DSG1,RAP1A,SERPIN89,PRKAR2A,SCP2....

Here are some parts from the answers of the three different reasoning Engines :

Engine 1




Engine 2



Engine 3




and finally from Engine 3, note the mention on Toxic substances