Metabolite-Detecting Gene Expression After Exercise in CFS, MS, and Controls

[oceanblue]

I'm out of my depth biologically but I thought I'd throw this out there: with the illness, symptoms and biology might not be in tandem. So if one overdoes it, one might actually be on a bit of a high, symptom-wise, and not take the hit, symptom-wise, till later; and indeed, symptoms weren't peaking till 8-48 hours later. So perhaps with correlations between symptoms and receptors, one doesn't need to just compare simultaneously but also look at other time points.

Unfortunately, a lot of data is also lost because one doesn't have continuous readings - just readings from a few time-points (not equally spread out) after the exercise. Also, there are more symptoms than just MF, PF and pain.

MF, PF and pain were chosen by the authors as they were focusing on pain and fatigue perception. It's possible that symptoms are delayed, but note that MF, PF and pain correlated with gene expression in the larger 2011 paper, which is why it bothered me they didn't in this paper. It's the correlation between biological changes and symptoms that made the first paper so compelling.

 

[Dolphin]

Thanks Oceanblue.

It was a pity they had a few patients overlapping from another study. I wonder why they did that.

I don't believe there was any discussion or investigation of this finding which would have been interesting:

Results: No gene expression changes occurred following exercise in Controls. In 71% of CFS
patients, moderate exercise increased most sensory and adrenergic receptors and one cytokine
genes transcription for 48 hours. These post-exercise increases correlated with behavioral
measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic ?-2A
receptors transcription was decreased at all time points after exercise; other genes were not altered.
History of orthostatic intolerance was significantly more common in the ?-2A decrease subgroup.

from:

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC.
J Intern Med. 2012 Jan;271(1):64-81. doi: 10.1111/j.1365-2796.2011.02405.x. Epub 2011 Jul 13.

I suppose this is the problem when one publishes papers close together and one isn't sure that one will definitely be published before another paper is published.
I'm guessing this happens more in other fields where researchers can be more prolific.

 

[oceanblue]

In terms of matching people (whether controls or people with other illness groups), it might be good if researchers used pedometers/actometers/other motion sensing device for this (say over a week). Although I suppose the problem is that you would need to discard some of your controls so you would need to have extra ones, which might not be so easy to get.

That's a good idea, and would provide some quantative data on how well matched the patients are. In practice, it may be very difficult to find healthy controls that are truly matched to CFS patients, unless those pateints are mildly affected, in which case there may be questions about how appicable the findings are to more severly affected patients. That's why I'd like to see exertion matched on RPE between controls and patients (so long as the RPE was set at a level that would normally cause PEM etc to patients). Another possibility is to use activity-matched patients with a different illness. MDD would be particularly interesting as their inactiity is presumably linked to motivation rather than underlying pathology.

Of course, it's also what they were trying to do with the fatigued MS controls; actometer data would have been helpful to establish if activity levels were indeed comparable (the disability scale information they provided suggested these patients might have been quite active, but we don't know for sure). It's a pity that the difference between MS and CFS wasn't more clear cut (adrenergic the same for both and different from controls, metabolite-sensing different between CFS and MS).

I was pleased to see the Lights mention this study although it's not the one issue they mention with regard to metabolite-detecting receptors:
...
It would probably be good if the Lights could measure postexercise levels of intramuscular pH in tandem with other research.

Now that would be a very interesting study.

 

[oceanblue]

It was a pity they had a few patients overlapping from another study. I wonder why they did that.

The overlap was with the 2009 pilot. They didn't explicitly say there was no overlap with larger the 2011(e)/2012 paper; if I was them I wouldn't have left any patients out of that study to get the sample size as big as possible - so perhaps patients overlapped wtih that one too. I think all of the patients in this MS study were tested well before the other paper came out:

Patients with CFS
and patients with MS were recruited from local clinical practices that specialized
in these populations and were tested between July 2006 and November 2009

 

[Dolphin]

I contacted the authors. I was told the legend for figure 1 is black circle = pain; open triangle = mental fatigue; solid triangle = physical fatigue.

 

[oceanblue]

True: the answer would be to do bigger studies but unfortunately the Lights have ruled that out.

This was based on some earlier comments by Cort and Alan Light, but it seems from Cort's NIH 2012 Review that I got that wrong and bigger studies are underway, though probably not with MS patients:

The NIH Backs the Lights Big Time

Title - POST-EXERCISE ION CHANNEL GENE EXPRESSION BIOMARKERS IN CFS
Investigator - Kathleen Light at the University of Utah
Duration 2011-2014
Money Spent Thus Far $336,000

Description - With their gene expression studies focusing on genes known to act up when our muscles get tired, the Lights have basically created a field of their own... This study is a major expansion of their last grant which looked at the gene expression of receptors known to become activated during exercise...

This grant just about doubles their study size (up to 140 patients!), tacks on a full genomic array (instead of selected genes), takes a deeper look at a collection of genes of special interest, and adds another control group prostate cancer patients with fatigue. Like the Natelson study, this is a validation study plus; its first goal will be to validate the results of the old study with new patients and then hopefully expand on it.

 

[Bob]

Cort Johnson has a new article that discusses and interprets the Lights' 2012 paper...

A “Fatigue” Disorder No More? – What Multiple Sclerosis Taught Us About Fatigue and Chronic Fatigue Syndrome
By Cort Johnson
November 6, 2014
http://www.cortjohnson.org/blog/201...sclerosis-taught-us-chronic-fatigue-syndrome/


Some thought provoking & interesting excerpts...

"The expression levels of two genes (P2X4/TRPVI) that bounced up immediately after exercise in the ME/CFS group, and then stayed elevated for 48 hours were associated with post-exertional malaise. One of them, P2X4, was directly associated with both the increased fatigue and pain experienced after exercise in the ME/CFS patients. These are muscle metabolite sensing genes that assess the levels of factors associated with muscle fatigue and damage."

"Despite their enormous fatigue, the MS patients mostly sailed through the exercise period. Their physical and mental fatigue did rise 8 hours after exercise, but both was back to baseline at 24 and 48 hours. At no point did exercise increase their pain levels. The Chronic Fatigue Syndrome patients, on the other hand, immediately experienced increased levels of physical and mental fatigue and pain after exercise – which were still present 8, 24 and even 48 hours later."

"After exercise the MS patients looked more like healthy controls than the ME/CFS patients. The levels of the metabolite sensing genes actually dropped in both the MS and healthy controls eight hours after exercise and then rebounded to normal levels. The Lights called this response evidence of a “well-regulated sensory pathway”."

"The Lights suggested that even normal levels of muscle metabolites may be sparking an overexpression of metabolite sensing genes in people with ME/CFS. Those genes are there to alert the central nervous system that the muscles are overworked and that it’s time to induce fatigue and pain to keep them from being injured."



Just for handy reference, these are the details of the paper...

Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls
Andrea T. White, Ph.D., Alan R. Light, Ph.D., Ronald W. Hughen, Timothy A.VanHaitsma, M.S., and Kathleen C. Light, Ph.D.
Psychosom Med. 2012 January ; 74(1): 46–54.
doi:10.1097/PSY.0b013e31824152ed.
http://journals.lww.com/psychosomat...s_in_Metabolite_Detecting,_Adrenergic,.9.aspx


And, for reference, these are some of the Lights' similar papers:

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC
J Intern Med. 2011 May 26.
doi: 10.1111/j.1365-2796.2011.02405.x.
[Epub ahead of print]
26 May 2011
http://www.ncbi.nlm.nih.gov/pubmed/21615807
http://forums.phoenixrising.me/inde...seline-and-following-moderate-exercise.10638/

Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome
Kathleen C. Light, Andrea T. White, Scott Tadler, Eli Iacob, and Alan R. Light
Pain Research and Treatment
Volume 2012 (2012), Article ID 427869
http://dx.doi.org/10.1155/2012/427869
http://forums.phoenixrising.me/index.php?threads/kathleen-light-new-fibro-me-cfs-review.13857/