PEM & the role of elastase, complement C4a and interleukin-1β

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Tate Mitchell posted this to co-cure today

[if: Another Metzger study. Love that they found PEM in all CFS subjects, but am not sure how they measured it. I can't access the full text. I'm a bit confused as they said "neither exercise bout altered elastase activity, IL-1β or complement C4a split product levels", but also said, "Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS."

I'm also not clear what the difference is between the 2 types of exercise and when they measured for PEM. Look forward to the full text.

Love the use of the word "biomarker"

Love that they're calling for more research into measuring PEM. ]

Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β

Journal of Internal Medicine, Volume 267, Number 4, April 2010 , pp. 418-435(18)

Nijs, J.; Van Oosterwijck, J.; Meeus, M.; Lambrecht, L.1; Metzger,
K.2; Frmont, M.2; Paul, L.3

(Vrije Universiteit Brussel, Brussels; University College
Antwerp, Antwerp; University Hospital Brussels, Brussels; Private
Practice for Internal Medicine, Gent/Aalst; and RED Laboratories N.V.,
Zellik; Belgium, and University of Glasgow, Glasgow, UK).

http://www.ingentaconnect.com/content/bsc/jint/2010/00000267/00000004/art00009


Abstract:

Objectives. Too vigorous exercise or activity increase frequently
triggers postexertional malaise in people with myalgic
encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary
characteristic evident in up to 95% of people with ME/CFS. The present
study aimed at examining whether two different types of exercise
results in changes in health status, circulating elastase activity,
interleukin (IL)-1β and complement C4a levels.

Design. Comparative experimental design.

Setting. University.

Subjects. Twenty-two women with ME/CFS and 22 healthy sedentary
controls Interventions: participants were subjected to a submaximal
exercise (day 8) and a self-paced, physiologically limited exercise
(day 16). Each bout of exercise was preceded and followed by blood
sampling, actigraphy and assessment of their health status.

Results. Both submaximal exercise and self-paced, physiologically
limited exercise resulted in postexertional malaise in people with
ME/CFS.


However, neither exercise bout altered elastase activity,
IL-1β or complement C4a split product levels in people with ME/CFS or
healthy sedentary control subjects (P > 0.05).


Postexercise complement C4a level was identified as a clinically important biomarker for
postexertional malaise in people with ME/CFS.


Conclusions. Submaximal exercise as well as self-paced,
physiologically limited exercise triggers postexertional malaise in
people with ME/CFS, but neither types of exercise alter acute
circulating levels of IL-1β, complement C4a split product or elastase
activity. Further studying of immune alterations in relation to
postexertional malaise in people with ME/CFS using multiple
measurement points postexercise is required.


Keywords: chronic fatigue syndrome; exercise; fibromyalgia; immunity;
pain; postexertional malaise

Document Type: Research article

DOI: 10.1111/j.1365-2796.2009.02178.x

Affiliations: 1: Private Practice for Internal Medicine, Gent/Aalst 2:
RED Laboratories N.V., Zellik, Belgium 3: Nursing and Health Care,
Faculty of Medicine, University of Glasgow, Glasgow, UK
 

Hope123

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Yes, I'd like to see it as well. One problem with cytokine research in CFS is that the researchers often don't have the money to look at a full panel of cytokines -- there are many, many cytokines. Klimas does some good work in this area but even her studies only cover about 10-20 whereas a small paper I saw about Sjgoren's tested for 25 different ones.
 

lostinthedesert

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Not just what but when

I'm wondering when they took their post-exercise samples. I think that if they took several samples going out at least as far as 48 hours, they may have seen some changes.
 
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I wanted to point out a couple of interesting things about C4a that they found in this paper:

1. Sorensen tested patients 6 hours after exercise and found a steep rise in C4a that corresponded with PEM. In the Nijs paper they tested participants 1 hour after exercise (for whatever reason) and didn't find an increase of C4a. However, they explicitly state in the paper that they didn't test after 6 hours so there's no evidence in their findings that C4a won't rise 6 hours after exercise. What makes their findings most interesting is that -

2. They tracked C4a levels 24 hours after exercise and found that an increase in "complement C4a level was strongly related to the increase in pain and fatigue 24 hours following the [exercise]." Additionally (and most interestingly) they found, "The level of complement C4a following submaximal exercise was identified as a clinically important biomarker in people with ME/CFS."

We need all the biomarkers we can get in the CFS/ME world, so bravo.
 
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ME research UK study - Exercise, immunology and pain

http://www.meresearch.org.uk/research/projects/malaise.html
Journal of Internal Medicine: http://www3.interscience.wiley.com/journal/122649385/abstract?CRETRY=1&SRETRY=0

Exercise, immunology and pain

Authors
Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Fremont M, Paul L

Institution
Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels; and Division of Musculoskeletal Physiotherapy, Department of Health Sciences, University College Antwerp, Antwerp, Belgium

Objectives
Too vigorous exercise or activity increase frequently triggers postexertional malaise in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary characteristic evident in up to 95% of people with ME/CFS. The present study aimed at examining whether two different types of exercise results in changes in health status, circulating elastase activity, interleukin (IL)-1b and complement C4a levels.

Design
Comparative experimental design.

Setting
University.

Subjects
Twenty-two women with ME/CFS and 22 healthy sedentary controls.

Interventions
Participants were subjected to a submaximal exercise (day 8) and a self-paced, physiologically limited exercise (day 16). Each bout of exercise was preceded and followed by blood sampling, actigraphy and assessment of their health status.

Results
Both submaximal exercise and self-paced, physiologically limited exercise resulted in postexertional malaise in people with ME/CFS. However, neither exercise bout altered elastase activity, IL-1b or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects (P > 0.05). Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS.

Conclusions
Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1b, complement C4a split product or elastase activity. Further studying of immune alterations in relation to postexertional malaise in people with ME/CFS using multiple measurement points postexercise is required.

Publication
Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. Journal of Internal Medicine 2010; 267: 418-35.

Funding Acknowledgements
The study was funded by ME Research UK, a national charity funding biomedical research into ME/CFS. Jessica Van Oosterwijck was financially supported by grant no. OZR1596 from the research council of the Vrije Universiteit Brussel, Brussels, Belgium. Mira Meeus is financially supported by the Research Foundation Flanders, Belgium.

Comment by ME Research UK
The cardinal symptom of ME from the traditional literature was profound, post-exertional loss of muscle power (fatigability) associated with muscle pain, tenderness and swelling. And still today, post-exertional symptoms are key; the NICE Clinical Guideline of 2007 informs GPs that, for a diagnosis of ME/CFS to be made, fatigue characterised by post-exertional malaise typically delayed, for example by at least 24 hours, with slow recovery over several days has to be present. It is worth emphasising that post-exercise symptoms are not present in other fatigue-related disorders, and that their very presence greatly helps to distinguish ME/CFS from, say, major depressive disorder.

Given this, it is surprising that so little is known about muscle physiology, the role of exercise, or indeed about patients responses to exercise in a laboratory setting. One research group, however, has a long-standing interest in this aspect: Prof. Jo Nijs and his colleagues at Vrije Universiteit Brussel, and University College Antwerp in Belgium. With funding from ME Research UK, these researchers have been investigating immunological responses to exercise, and the effect of exercise on these responses, and their latest scientific report has just been published in the Journal of Internal Medicine (April 2010).

Prof. Nijs and his team were looking at whether different exercise regimes trigger increases in elastase activity, IL-1b and complement C4a levels, and whether changes in these parameters might be associated with exacerbations of symptoms following exercise in people with ME/CFS. The experimental group consisted of women with ME/CFS plus ACR-defined chronic widespread pain (a group the researchers believed would more closely represent ME/CFS patients in the community in whom pain is a major symptom), and 22 non-athletic female controls. Participants completed the two exercise tests, one week apart. At each visit they were required to fill out a range of outcome measure questionnaires, and had blood samples taken for determination of the immune variables, such as elastase activity and G-actin cleavage. One hour after exercise testing, patients again provided samples and outcome information, and 24 hours later again reported their symptoms.

The first exercise test involved a well-studied submaximal exercise protocol using a bicycle. The second exercise was a self-paced and physiologically limited bicycle exercise with three safety breaks; the exercise duration was determined using the principles of pacing self-management as commonly used in people with ME/CFS, and the activity duration estimated by the participants was then further reduced to account for typical overestimations.
The results were interesting on a range of levels. As regards post-exercise symptoms, the submaximal exercise and the self-paced, physiologically limited exercise both triggered symptoms, such as pain, after 1 and 24 hours, highlighting that exercise needs to be employed with caution in ME/CFS patients. Looking at the immunology, however, neither type of exercise altered circulating levels of IL-1b, complement C4a split product or elastase activity a most unexpected result. Most fascinatingly, the complement C4a level, measured after exercise, was identified as a possible biomarker for the development of post-exertional symptoms in people with ME/CFS.

Looking at the larger picture, much of the current thinking about the role of exercise in CFS and ME is driven by models of deconditioning, and the notion that regular exercise will be beneficial. And overall that is true; regular exercise is good for us all. But we already know that too vigorous exercise or activity can triggers post-exertional symptoms in most people with ME/CFS. And there is some evidence that these patients respond to an exercise challenge with an enhanced complement activation, increased oxidative stress, and an exaggeration of resting differences in gene expression profile in peripheral blood mononuclear cells. So, it is entirely possible, perhaps even likely, that over-exercising causes harm, simply because something is organically wrong with muscle metabolism. What value exercise programmes in these circumstances?

In fact, the characteristic delay in muscle recovery after exercise (with pain and fatigue days afterwards) in ME/CFS is a phenomenon which few have studied, and which the deconditioning hypothesis does not address. Many questions remain. For instance, a few studies have reported abnormal mitochondrial structure and enzyme function and/or evidence of viral activity in skeletal muscle tissue in some patients with ME/CFS are viral particles interfering with the muscles ability to carry out specialised functions? Again, post-exercise muscle pain is a widespread symptom but why is there muscle pain, and could a state of energy depletion during exercise and the development of noxious free radicals be responsible? And, most pertinently, how many ME/CFS patients have ever had a proper clinical examination of their painful and tender muscles by a healthcare professional?
 

Cort

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I wanted to point out a couple of interesting things about C4a that they found in this paper:

1. Sorensen tested patients 6 hours after exercise and found a steep rise in C4a that corresponded with PEM. In the Nijs paper they tested participants 1 hour after exercise (for whatever reason) and didn't find an increase of C4a. However, they explicitly state in the paper that they didn't test after 6 hours so there's no evidence in their findings that C4a won't rise 6 hours after exercise. What makes their findings most interesting is that -

2. They tracked C4a levels 24 hours after exercise and found that an increase in "complement C4a level was strongly related to the increase in pain and fatigue 24 hours following the [exercise]." Additionally (and most interestingly) they found, "The level of complement C4a following submaximal exercise was identified as a clinically important biomarker in people with ME/CFS."

We need all the biomarkers we can get in the CFS/ME world, so bravo.
Thanks for the analysis - bump!