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Gene expression alterations at baseline and following moderate exercise

Dolphin

Senior Member
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oceanblue said:
This matters, because the genes chosen for study have increased expression for strenous exercise in healthy controls:

Initial experiments with normal subjects indicated that mRNA for [genes in this 2011 study] was upregulated at 8 and 24 hours after strenuous exercise. (from 2009 pilot study)
Well spotted, oceanblue.

The next line of the quote says:
The mRNA increases returned to near normal levels 48 hours after strenuous exercise.38

38. Light AR, Hughen RW, Zhang J, White A, Light KC,
Jensen BT, Fitschen KL: Molecular receptors for pH found
on sensory neurons are also found on mouse and human
leukocytes and increase 8-48 hours post-exercise in both
control subjects and fibromyalgia and chronic fatigue patients.
Soc Neurosci 510:3, 2007
The 48 hour timepoint might be the most important one.
 

oceanblue

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Well spotted, oceanblue.

The next line of the quote says:
"The mRNA increases returned to near normal levels 48 hours after strenuous exercise.38"

The 48 hour timepoint might be the most important one.
Good point, I hadn't noticed that. But even so, that leaves 3 of the 4 time points as not relevant (and they used AUC, the sum across all 4 time points, for most analyses).

Fundamentally, what I don't understand is why they didn't use an exercise test that is relevant to the real-world exertions that provoke PEM for people with CFS. 'Moderate exercise' is way more than most people with CFS need to provoke PEM, or indeed can manage. If you can mange moderate exercise (as 'limited a little') you probably score over 80 on the SF36 PF scale!
 

Dolphin

Senior Member
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Fundamentally, what I don't understand is why they didn't use an exercise test that is relevant to the real-world exertions that provoke PEM for people with CFS. 'Moderate exercise' is way more than most people with CFS need to provoke PEM, or indeed can manage. If you can mange moderate exercise (as 'limited a little') you probably score over 80 on the SF36 PF scale!
I certainly wouldn't be rushing to have the test (but then I'm severely affected). Saying that, hopefully it will give useful knowledge about the condition. I'm no expert but sometimes "challenge tests" both in research and/or even in clinical practice are a big unusual e.g. you get a big dose of ACTH or a buspirone challenge test (can't say I know too much about the latter).
 

oceanblue

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I can certainly see the need to make the challenge big enough to ensure you are going to get a result (PEM in this case) but this still fails there own logic of trying to find something closer to real world situations (they deliberately avoided maximal exercise tests for this reason). And crucially, the level of challenge varied with severity: maybe it was moderate for the least affected but extreme for the most severely affected. This gives you unreliable data, particularly as the level of expression changes with level of exercise challenge in healthy controls. Maybe setting exercise based on a given level of RPE exertion would give a more appropriate test.

I still think what they are trying to do is very important, and their secondary analysis using matched RPE indicates they've found something real, but the methodolgy needs refining. The CAA (who funded this work) pointed out the need for replication by other groups; hopefully this will happen and other researchers will refine the exercise challenge.
 

WillowJ

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I think the RPE is influenced by neuromuscular channelopathy (Siemionow 2004, Jammes 2009 & 2005, Pietrangelo 2009, Whistler 2005), which might help. Really it's a confounding factor (unless any of those gene products disrupt these neuromuscular ion channels), but it confounds in the direction of presumably increasing RPE selectively in the ME/CFS sample.
 

Snow Leopard

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The problem with this approach is that for the most severely affected patients (bedbound/housebound) 70% of max heart rate for 25 mins is way, way more than moderate exercise...

Is it way more than "moderate exercise" based on their fitness and day to day activity levels, or way more because of their disease?

The fact is that you have to do "way more" to provoke such a response when the study size is small. The bias with exercise studies is you are unlikely to have more severely affected patients, so "moderate" levels of exercise are higher. I really wish figures such as SF-36 PF scores and employment status were published though.
On the other hand, I agree the controls should be carefully matched based on fitness levels and sedentary activity levels (measured with actometers).
 

Sean

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On the other hand, I agree the controls should be carefully matched based on fitness levels and sedentary activity levels (measured with actometers).

Sounds good to me. With lots of objective post-exertional testing, from start to finish.
 

oceanblue

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Is it way more than "moderate exercise" based on their fitness and day to day activity levels, or way more because of their disease?

The fact is that you have to do "way more" to provoke such a response when the study size is small. The bias with exercise studies is you are unlikely to have more severely affected patients, so "moderate" levels of exercise are higher. I really wish figures such as SF-36 PF scores and employment status were published though.
On the other hand, I agree the controls should be carefully matched based on fitness levels and sedentary activity levels (measured with actometers).
Way more because of activity levels: 25 mins @ 70% max heart rate is not appropriate for anyone who has been rated housebound/bedbound (as applied to some in this study). I'm arguing that the challenge needs to be strong enough to provoke the PEM that this study focuses on, but not so strong that it confounds the whole study by pushing people to extreme exercise. Matching controls on fitness levels as you suggest would help.
 

WillowJ

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is there a way we can use other disease groups as controls, in order to match sedentary-ness, without introducing inappropriate confounding? actually, we could then know whether the test was diagnostic and whether the effect was ME/CFS-specific. this would be better than comparing to healthy sedentary population in this regard, wouldn't it?
 

Dolphin

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is there a way we can use other disease groups as controls, in order to match sedentary-ness, without introducing inappropriate confounding? actually, we could then know whether the test was diagnostic and whether the effect was ME/CFS-specific. this would be better than comparing to healthy sedentary population in this regard, wouldn't it?
It may not be perfect but this group, to their credit, is looking at other disease groups:
We have shown in a recently submitted manuscript that these gene markers are not similarly
increased in patients with MS who exhibit unexplained increases in fatigue (White, A.T., Light A.R.,
Hughen R.W., VanHaitsma T.A., and Light K.C. Differences in metabolite-detecting, adrenergic, and
immune gene expression following moderate exercise in multiple sclerosis, chronic fatigue syndrome,
and healthy controls, submitted). We also have preliminary data indicating that these genes are not
increased before or after exercise in patients with unexplained fatigue who have advanced prostate
cancer. Furthermore, the observations from this study on the subset of controls tested while on
antidepressants prescribed for mild clinical depression suggest that these genes are not increased in
medication-responsive depression; we are currently examining patients with moderate to severe
medication-refractory depression to reinforce this tentative finding.
 

oceanblue

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is there a way we can use other disease groups as controls, in order to match sedentary-ness, without introducing inappropriate confounding? actually, we could then know whether the test was diagnostic and whether the effect was ME/CFS-specific. this would be better than comparing to healthy sedentary population in this regard, wouldn't it?
As Dolphin points out, the authors have submitted a paper on this and it will be interesting to see the detailed results. My concern would be on how sedentary they are: MS can cover a very wide range of abilities. But if they are appropriately matched then these MS results would be compelling evidence of a unique process to CFS/ME. However, the cytokine gene expression profile may not be comparable as this would be expected to be disturbed in MS anyway.
 

WillowJ

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It may not be perfect but this group, to their credit, is looking at other disease groups:

I do remember now that you posted this. Also there's a group that compares to liver disease, but I can't think of any citations right now or what they study.
 

WillowJ

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However, the cytokine gene expression profile may not be comparable as this would be expected to be disturbed in MS anyway.

wouldn't that help us know what was diagnostic? and also help demonstrate similarity of ME/CFS to MS (rather than have it thought to be more appropriately compared to anorexia nervosa)?
 

Dolphin

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I do remember now that you posted this. Also there's a group that compares to liver disease, but I can't think of any citations right now or what they study.
With regard to liver disease, I think you're thinking of Julia Newton's research team who have compared the two e.g.:

e.g. free full text: http://qjmed.oxfordjournals.org/content/100/8/519.long

Symptoms of autonomic dysfunction in chronic fatigue syndrome.

QJM. 2007 Aug;100(8):519-26. Epub 2007 Jul 7.

Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE.

Fatigue Interest group and Liver Research Group, Institute for Cellular Medicine, University of Newcastle, Newcastle, UK. julia.newton@nuth.nhs.uk

Abstract
BACKGROUND: Chronic fatigue syndrome (CFS) is common and its cause is unknown.

AIM: To study the prevalence of autonomic dysfunction in CFS, and to develop diagnostic criteria.

DESIGN: Cross-sectional study with independent derivation and validation phases.

METHODS: Symptoms of autonomic dysfunction were assessed using the Composite Autonomic Symptom Scale (COMPASS). Fatigue was assessed using the Fatigue Impact Scale (FIS). Subjects were studied in two groups: phase 1 (derivation phase), 40 CFS patients and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis.

RESULTS: Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of CFS or primary biliary cirrhosis (PBC), and correlated with severity of fatigue. Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.86-0.99) and a negative predictive value of 0.84 (0.70-0.93) for the diagnosis of CFS.

DISCUSSION: Autonomic dysfunction is strongly associated with fatigue in some, but not all, CFS and PBC patients. We postulate the existence of a 'cross-cutting' aetiological process of dysautonomia-associated fatigue (DAF). COMPASS >32.5 is a valid diagnostic criterion for autonomic dysfunction in CFS and PBC, and can be used to identify patients for targeted intervention studies.
 

oceanblue

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wouldn't that help us know what was diagnostic? and also help demonstrate similarity of ME/CFS to MS (rather than have it thought to be more appropriately compared to anorexia nervosa)?
The aim is to find out if the gene expression changes after exercise are part of ME/CFS. MS and other illnesses such as RA could provide suitable sedentary controls but with many diseases you would expect a non-normal cytokine profile because of infection/autoimmunity etc, which would confound the results. It would make it very hard to intepret any differences/similarities in cytokine profile between MS, say, and ME/CFS.
 

oceanblue

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Need for replication of these findings

I think that, along with XMRV and Riuximab, this report of increased gene expression in response to exercise is amongst the most interesting findings to emerge about CFS. However, as with XMRV and Rituximab, replication is crucial.

The biggest concern over this study relates to the higher exertion levels of CFS patients than controls, as has been extensively discussed on this thread. The authors had indicated that submitted research would demonstrate that in response to exercise MS patients showed no change in the expression of the genes that increased post-exercise in CFS patients. This would go some way to demonstrate the changes were unique to CFS and not related to deconditioning, particularly if the MS patients were well-matched with the CFS ones in terms of activity levels.

We have shown in a recently submitted manuscript that these gene markers are not similarly
increased in patients with MS who exhibit unexplained increases in fatigue
(White, A.T., Light A.R.,
Hughen R.W., VanHaitsma T.A., and Light K.C. Differences in metabolite-detecting, adrenergic, and
immune gene expression following moderate exercise in multiple sclerosis, chronic fatigue syndrome,
and healthy controls, submitted).

This submitted paper on MS patients has now been published and while it shows that metabolite receptor gene expression is not increased in response to gene expression, it also shows that the adrenergic recepotor genes are similarly increased in MS and CFS patients. Which makes it far less conclusive. It's not clear how well matched the MS patients were to the CFS patients.

Furthermore, the moderate-to-strong link found between gene expression and fatgiue and pain scores across all the genes implicated in this (2011) paper was not replicated in the new MS/CFS paper. The only correlation found was for a single adrenergic gene, P2X4, and then only for pain and not for fatigue. It was this correlation between gene expression and fatigue and pain that made the findings of this 2011 paper so compelling.

Replication studies have not been kind to the XMRV findings to date, though the largest and most rigorous (Lipkin) study has yet to report. Replication of the Rituximab findings are planned by its authors and at least one other group. The authors of these gene expression findings have made it clear they believe their work to date is sufficient:
We believe the published studies we have provided are sufficient to demonstrate that at least some genes that are involved in fatigue detection [and immune cell modulation] are dysregulated in CFS, and that this may contribute to some of their symptoms.
As the CAA, who funded this study say "As with any research, these findings will need to be replicated by another research group in another group of CFS (and FM) patients", to establish that these gene expression are a real and important link to fatigue and pain in CFS. Hopefully other groups will do exactly this.