Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS, Arnaud Germain, Maureen R. Hanson et al, 2022

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Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Post-exertional malaise (PEM) is a hallmark symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

We monitored the evolution of 1,157 plasma metabolites in 60 ME/CFS cases (45 females, 15 males) and in 45 matched healthy control subjects (30 females, 15 males) before and after two maximal Cardiopulmonary Exercise Test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients.

Four timepoints allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of ME/CFS cases compared to the healthy control group.

Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds.

Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites.

The effects of exertion in the ME/CFS cohort predominantly highlighted lipid- as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions.

The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different.

The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM.

Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component to the homeostasis of many organs in the body, including the brain.

 

Spotted on twitter via Dr. Maureen Hanson who comments:

The Cornell NIH ME/CFS Center's major plasma metabolomics study is now available as an in-press preview. An easier-to-read final version will be available at the journal site in about two weeks.

 

I continue to be puzzled by the interpretation of the 2 Day CPET in relation to PEM.
I would have thought that anyone with ME who got PEM from the first maximal exercise would want to avoid a second one. If a feel lousy enough not to be able to carry on with normal daily activities I am pretty sure I wouldn't want to do an exercise test.

So far I cannot find any indication in the paper as to whether patients experience PEM. If not the results may be interesting but I am not sure what they have to do with PEM.

I can understand the 2 Day CPET as a way of showing that one bout of exercise may lead to alterations in physiology that can be judged by a poorer performance the next day. What I am less clear about is the value of looking at before and after metabolites for two consecutive tests. Presumably if the metabolites change in an interesting way relevant to generating PEM that would occur after the first test.

A different shift between before and after for a second test might reflect a shift in physiology but then there is the question of whether this is just a reflection of the person feeling ill - if they do, and that seems unclear anyway.

The other thing is that, although I find this sort of study hard to follow, it seems that the results indicate that the vast majority of metabolites behave pretty normally in PWME. I think it is important that this is said if so. If the results strongly suggest that metabolism as a whole is not abnormal enough to explain any major change in ability to do things then that is important to know. It indicates that the problem of PEM lies elsewhere.

 

I will read this properly later. In the meantime: looking at the change in glutamate-related pathways, maybe the exertion intolerance in ME/CFS is more accurately an intolerance of being stimulated?

Also, they found an alteration in “Phytanic Acid Peroxisomal Oxidation". I have a disease-causing variant in one gene which allows metabolizing phytanic acid. The associated disease is autosomal recessive so it doesn't manifest, but the variant does reduce enzyme activity. It sounds like this might matter in ME/CFS. Phytanic acid is introduced into the body mainly by eating dairy products and meat from ruminant animals.

 

(Sorry if this is irrelevant and I'm not bringing anything new, my memory has holes...) I have the impression that the process leading to PEM sometimes resembles reaching a threshold of effort (which may be variable within a pwme and between pwme) and/or to something that accumulates (physiological deficiencies) over the days until a breaking point.

Question: Even if the patients in the study may not have had a PEM after day 1, could the metabolites found still inform about the process initiated towards a possible PEM ? Maybe some study patients finally got PEM on day 3 or 4, e.g. ?

 

As far as I could see, while the controls were considered to be sedentary, there is nothing to say that they had a similar activity level to the patients, so I don't think we can necessarily rule out that a reason for the differences found could be differences in activity levels between patients and controls.

 

Are there disruptions in plasma responses in other fatigue syndromes (cognitive and physical)?

 

I am presuming they all have PEM as part of their functioning, in the supplementary material, they show the range of severity on the Bell’s Disability scale which encompasses getting worsening symptoms with the level of exercise, most were in the moderate to severe range at the start of testing but would be interesting to know their outcome.

I found some of the results interesting i.e. there is no general state of hypometabolism but especially the production of these unknown metabolites, but not enough to be considered biomarkers. I was unsure if their metabolite analyser just didn’t have the power to identify them or they are unique. Will be very interesting to see other scientists involved in metabolomic research discuss their significance.

 

If you want to measure the impact of PEM on metabolism (and hence try to explain the poorer performance) during the second test, you need two tests.

That's why they have multiple time points - comparison to before the first test for example. Metabolic correlates of "feeling ill" are still useful.

But I'm not completely sure what you mean by "just a reflection of the person feeling ill"? And I'm saying that as someone who has participated in a published 2 Day CPET study.

I think you have unrealistic expectations of the results, particularly when the sample size is limited - a standard that wouldn't be expected with a similar study of other conditions (such as muscular dystrophies or peripheral neuropathies). We already know ME is not a rare genetic disease that causes a hypo-disruption in a specific metabolic pathway (eg a glycogen storage disease). We have known that ME is not a generalised "hypometabolic" disease for a long time.

What we are looking for are things such as a relative shift the ratio of one metabolic pathway compared to others which is a result of another underlying problem, or an increased build up of metabolites that could increasingly stimulate metabosensitive afferents.
Though obviously this is limited by the fact that we are testing plasma, rather than what is going on directly in specific cell types and hence requires increased spill-over into, or consumption into plasma.

There were also differences in carnitine metabolism which has also been found in other (non-exercise) studies, though I increasingly think this is an effect, rather than a cause.

Most likely yes, but similarly subtle like in ME/CFS patients.[/quote]

 

I can see that but did they demonstrate a poorer performance to explain? If they didn't I don't see the point.

There seems to me to be a confusion between PEM as defined as the symptom complex that occurs after exertion and PEM as defined as some fall in ability to do work - a sort of delayed fatiguability. From what I understand of the symptom of PEM these are two quite different things.

All sorts of other stimuli that might make people feel ill might have a similar effect on reducing ability to do work - with no connection in terms of specific metabolic pathways.

 

I am guessing that is arriving in a second paper (Hutan already pointed out the lack of the CPET data), though the key point is that over 10 prior studies have all found such a difference, so I don't think it is unreasonable to expect there will be similar differences in this study.

Can you explain what you mean by this?

How can feeling ill reduce ability to do work during a CPET without alteration in utilisation of metabolic pathways?

On a ramped exercise test, the level of performance is basically forced until the test ends - a voluntary reduction in effort cannot occur during the test.

 

Figure 11 looks interesting. The unknown metabolite 15245 increases after each exercise test in controls, but in patients much less. Maybe this metabolite has an important role in recovering from exercise? Or maybe it's related to some branch of the energy production system that is not working?



This study like many others before it has again highlighted carnitine. I've been taking carnitine for a few years and think it allows me to be more active.

The study says

Carnitine is mainly used in the body to transport lipids into mitochondria, for energy production.

 

Yea carnitine is interesting to me. My wife has a neurological condition and low carnitine turned up in one of her tests; so she supplements with carnitine now.
Our daughter has disabling fatigue - a doctor has commented that it looks like ME.

If carnitine is relevant then Chris Ponting's GWAS study might pick up a genetic signal - although I seem to recall a comment (from Jonathan?) that the number/locations of (GWAS) "test points" may mean that GWAS doesn't actually pick it up.

 

Absolutely everything in this paper screams mitochondria.

Also, many people underestimate how incapacitating such aberrations in specific pathways can be; Ammonia Recycling taking a little break in a PEM state?

This doesn't come without a price tag.

 

Do you have information that demonstrates that changes to metabolites of the size we're seeing in these ME/CFS metabolomics studies can be reasonably assumed to translate into a substantial symptom burden and disability?

 

I participated in a 2 day CPET study with this group as a sedentary control and assume that study is reported in this paper.

As noted in the paper, subjects completed the Bell scale and SF-36 questionnaire. The Bell Scale goes from 0 to 100 where 100 is no symptoms at rest and 0 is continuous symptoms, bedbound, and needing full care. Figure B below gives the distribution of this cohort on the Bell Scale. And if I remember correctly, I reported what symptoms I was experiencing before and after the tests and out for a few days, possibly a week. I'd expect the symptom results to be reported as well at some point

 

So 15 patient participants self-rated themselves as 20 or below on the Bell scale. The descriptions for 20 and below on the scale are (my bolding)

I would argue that patients that, in theory, met the majority of those descriptions shouldn't have been able to take part in this study, and if they did then I'd query how ethical it was to allow them to do so.

 

Yes, I could send you my own metabolon results, then you could compare its results, many in itself toxic metabolites are comparable to ranges that are considered so in other diseases.

Urea cycle disorders, MSUD, etc.