Exertional Exhaustion [PEM] Evaluated by the Effects of Exercise on [CSF] Metabolomics–Lipidomics and Serine Pathway in [ME/CFS], 2025, Baraniuk

Exertional Exhaustion Post-Exertional Malaise, PEM Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Baraniuk, James N.

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest.

Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods.

Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS.

Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma.

The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

 

What are the implications of this finding?

 

How many «items» did they test? There are some high <0.05 p-values that could indicated random noise if they tested e.g. 200 items. You’d expect to find 10 items with p<0.05 in that case - assuming I have not misunderstood how p-values work?

Regardless, we need a replication study (with more females).

 

I am not sure I understand what was being looked for here and why. CSF might give an indication of what brain might have been doing but the samples were taken before and after physical exercise with arms and legs I presume.

 

Grateful for the study.

But damn, I really don’t think we should be defining PEM as Fatigue, nor saying fatigue is equivalent to a disabling limitation.

Disabling limitations can manifest without the subjective feeling of fatigue…

 

i appreciate Baraniuk writing this paper. If I recall correctly he got the big bucks from the NIH and he's doing the right thing by us here, wringing every last drop of possible information out of his samples. I particularly like the way he is using multiple different statistical techniques and presenting them, comparing and contrasting, so that no possible leads are missed / no finding is over-emphasised.

I do think the sample is too small to tell us anything definitive, but I don't want to finish on that point because it sounds dismissive and there are positives in the paper. Not least the use of exercise provocation (although nb the pre- and post-exercise people are different people, I think Hanson's approach of matching the same patient pre and post exercise is much better.)

The above notwithstanding, the idea that PWME are consuming/not producing metabolites during exercise is interesting, in contrast to the increased abundance of metabolites produced in healthy controls.

Baraniuk proposes a hypo-metabolic state (i.e. low metabolism) and aligns his findings with those of Naviaux. One touch I liked is describing Naviaux's "cell danger response" hypothesis in more concrete terms: "the cell danger response hypothesis may be analogous to the unfolded protein response, endoplasmic reticulum stress response, mitochondrial unfolded protein response, and related mechanisms."

Regular readers may be getting a familiar feeling here. Is Murph going to mention the Hwang study again? You bet I am. Enough information is pointing to the unfolded protein response that the fact we have just one study on it in mecfs is a problem. I have a good feeling about UPR as a mechanism to explain PEM; the pattern-matching parts of my brain are lighting up.

The other big point Baraniuk makes is that serine and phenylalanine are implicated clearly. That came through loud despite the sample size. Low phenylalanine post exercise in me/cfs has shown up before (the Germain urine metabolomics paper, Armstrong too). In healthy controls it rises after exercise. Serines are a precursor to phospholipids (including plasmalogens, my other current bugbear!) and dysregulated phospholipids are a common finding.

Overall this paper helps the science along gradually, emphasising that some findings could well be real signals that we should look at more.

I'm also more and more inclined to go back to the topic of meta-analysis : https://www.s4me.info/threads/mecfs-data-analysis-thread.37775/ There's no shortage of metabolomic studies coming in 2025. They will all be beset by noise and problems. But can we silence the noise through enough aggregation? And has AI come along enough to make the data analysis a bit quicker?

 

My question would be when were the post-exercise samples taken? If samples were taken either immediately or shortly after the exercise then I think it is more than a bit of a stretch to say that what is being seen is the effect of PEM, especially when he doesn't seem to get what PEM is.

 

Would this be detectable with an MRI if there are white matter lesions?

 

for what it's worth I also saw overexpressed proteasome complex subunits in LCLs from pwME in my PhD work

 

I couldn't understand this at first blush but it seems like the proteasome is a organelle-ish type thing in the cell that breaks down proteins; upregulation could be a sign of ER stress, is that the idea Daniel?

The Roles of the Ubiquitin–Proteasome System in the Endoplasmic Reticulum Stress Pathway
Junyan Qu 1,†, Tingting Zou 1,†, Zhenghong Lin 1,*
Editor: Kwang-Hyun Baek1

PMCID: PMC7913544 PMID: 33546413
Abstract

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response (UPR) as the unfolded proteins exceed the folding capacity of the ER due to the environmental influences or increased protein synthesis. ER stress can mediate many cellular processes, including autophagy, apoptosis and senescence. The ubiquitin-proteasome system (UPS) is involved in the degradation of more than 80% of proteins in the cells. Today, increasing numbers of studies have shown that the two important components of UPS, E3 ubiquitin ligases and deubiquitinases (DUBs), are tightly related to ER stress. In this review, we summarized the regulation of the E3 ubiquitin ligases and DUBs in ER stress.

 

Yep!

Can indicate or be elicited by other things of course, but yep. It makes sense together.

 

@Murph are you able to change the font to the standard one? I have a very hard time reading the skinny letters Thanks in advance!

 

@To anyone interested, I could send some relevant information, perhaps @DMissa ? The Ubiquitin Proteasome system has been one research target appearing for quite some time using machine learning and information retrieval methods. See attached from an email (september 2021) I sent to an undisclosed researcher :