Worse performance but normal oxidative phosphorylation capacity

lansbergen

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http://www.translational-medicine.com/content/pdf/1479-5876-8-93.pdf

Journal of Translational Medicine

Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity

Ruud CW Vermeulen1, Ruud M Kurk1, Frans C Visser1, Wim Sluiter2 and
Hans R Scholte3

1CFS/ME and Pain Research Center Amsterdam, Waalstraat 25-31, 1078 BR
Amsterdam, The Netherlands.
2Department of Neurology, Erasmus MC University Medical Center,
Rotterdam, The Netherlands.
3Department of Neuroscience, Erasmus MC University Medical Center,
Rotterdam, The Netherlands.

Abstract

Background: The aim of this study was to investigate the possibility that a
decreased mitochondrial ATP synthesis causes muscular and mental fatigue
and plays a role in the pathophysiology of the chronic fatigue syndrome
(CFS/ME).

Methods: Female patients (n=15) and controls (n=15) performed a
cardiopulmonary exercise test (CPET) by cycling at a continuously increased
work rate till maximal exertion. The CPET was repeated 24 h later. Before the
tests, blood was taken for the isolation of peripheral blood mononuclear cells
(PBMC), which were processed in a special way to preserve their oxidative
phosphorylation, which was tested later in the presence of ADP and
phosphate in permeabilized cells with glutamate, malate and malonate plus or
minus the complex I inhibitor rotenone, and succinate with rotenone plus or
minus the complex II inhibitor malonate in order to measure the ATP
production via Complex I and II, respectively. Plasma CK was determined as
a surrogate measure of a decreased oxidative phosphorylation in muscle,
since the previous finding that in a group of patients with external
ophthalmoplegia the oxygen consumption by isolated muscle mitochondria
correlated negatively with plasma creatine kinase, 24 h after exercise.
Results: At both exercise tests the patients reached the anaerobic threshold
and the maximal exercise at a much lower oxygen consumption than the
controls and this worsened in the second test. This implies an increase of
lactate, the product of anaerobic glycolysis, and a decrease of the
mitochondrial ATP production in the patients. In the past this was also found
in patients with defects in the mitochondrial oxidative phosphorylation
However the oxidative phosphorylation in PBMC was similar in CFS/ME
patients and controls. The plasma creatine kinase levels before and 24 h after
exercise were low in patients and controls, suggesting normality of the
muscular mitochondrial oxidative phosphorylation.

Conclusion: The decrease in mitochondrial ATP synthesis in the CFS/ME
patients is not caused by a defect in the enzyme complexes catalyzing
oxidative phosphorylation, but in another factor.
 

Dolphin

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I was reading some older stuff I printed out and never read and found that most of:
Lyndonville News Vol 8, Number 1, May 2011: http://www.davidsbell.com/LynNewsV8N1.html
is Norman Booth defending their* paper given the results of Vermeulen et al.

*Myhill S, Booth NE, McLaren-Howard J: Chronic fatigue syndrome and mitochondrial dysfunction. International Journal of Clinical and Experimental Medicine 2009, 2:1-16.
 

Sherlock

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I'm curious as to how these results would differ from merely having less O2 being delivered to the muscles?
 

Dolphin

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I submitted this comment back in Oct 2010. Unfortunately the journal never put it up. I thought I'd post it here now, just to put it on the record:


Title: Was this study sufficiently powered to find oxidative phosphorylation?

It is not desirable if a promising line of enquiry is prematurely ended by an underpowered study. Looking at Table 4 and in particular, rows 1, 2 and 4 where the figures go up for the controls from test 1 to test 2 and go down for the CFS/ME patients, I am left wondering whether a bigger study would have found a statistically significant difference. This is not a criticism of the researchers as, like all teams, I'm sure they would have preferred bigger samples but funding and other issues restrict what is possible for any one study. Also, the team in this case probably did not have advance data to do power calculations. It will be interesting to see if similar changes are evident in future studies* and whether pooled data would show differences even if individual studies don't reach the magical "statistical significance".

*if any researchers investigate this again - the volume of study in CFS is low and there is a range of issues to look at
 

Don Quichotte

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One of the problems with tests done in vitro is that they skip essential steps. What if the reason for decreased O2 consumption is not abnormalities of mitochondrial enzymes, but abnormalities of delivery of nutrients to the mitochondria (such as would happen in carnitine deficiency for instance?). what if there is a problem in the Kreb's cycle-leading to decreased CO2 production on the one hand, and decreased delivery of the products required for the Ox-Phos. reactions?
If I do a certain clotting test in a patient with hemphilia I will get completely normal results. Will that make me think that the patient isn't really bleeding? or that it is imaginary blood that I am seeing?
One of the problems with modern medicine is that it relies too much on such tests (which have their limitations) and too little on good-old bed-side assessment of the patient. if some one has clear-cut exercise intolerance which I can see using fairly simple parameters, why should I care what the exact mechanism is to make this assessment? Why should I invent ridiculous explanations which make no sense, just because I don't yet have a good understanding of the complex biological process which leads to those "unexplained" symptoms?
 

taniaaust1

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Methods: Female patients (n=15) and controls (n=15) performed a
cardiopulmonary exercise test (CPET) by cycling at a continuously increased
work rate till maximal exertion. The CPET was repeated 24 h later.
I do wonder with such studies if there is a biased in their patient selection (not something purposely done but something I think which could easily be happening in exercise studies). Most ME/CFS patients who have ME/CFS triggered off by exercise.. probably are far less likely to enrol in a study in which one exercises to maximum then those who have CFS with less issues with exercise. This could really affect studies and how they come out appearing.
 

Valentijn

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I do wonder with such studies if there is a biased in their patient selection (not something purposely done but something I think which could easily be happening in exercise studies). Most ME/CFS patients who have ME/CFS triggered off by exercise.. probably are far less likely to enrol in a study in which one exercises to maximum then those who have CFS with less issues with exercise. This could really affect studies and how they come out appearing.
These are probably proper ME patients - the CFS/ME Research Center is pretty much the only real ME center in the Netherlands that investigates and treats ME as presumptively biological. The lead researcher Ruud Vermeulen also has a good reputation in that regards (not be confused with Riem Vermuelen from the Academic Medical Center who equates ME/CFS with "medically unexplained symptoms" and psychosomatic illness).
 

alex3619

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One of the problems with tests done in vitro is that they skip essential steps. What if the reason for decreased O2 consumption is not abnormalities of mitochondrial enzymes, but abnormalities of delivery of nutrients to the mitochondria (such as would happen in carnitine deficiency for instance?). what if there is a problem in the Kreb's cycle-leading to decreased CO2 production on the one hand, and decreased delivery of the products required for the Ox-Phos. reactions?
If I do a certain clotting test in a patient with hemphilia I will get completely normal results. Will that make me think that the patient isn't really bleeding? or that it is imaginary blood that I am seeing?
One of the problems with modern medicine is that it relies too much on such tests (which have their limitations) and too little on good-old bed-side assessment of the patient. if some one has clear-cut exercise intolerance which I can see using fairly simple parameters, why should I care what the exact mechanism is to make this assessment? Why should I invent ridiculous explanations which make no sense, just because I don't yet have a good understanding of the complex biological process which leads to those "unexplained" symptoms?
There were several articles based on Myhill's research that show that the transfer of critical molecules into and out of the mitochondria is the major limiting factor. I do not have links handy, but the gist of the argument was the there is something wrong with the transporter channels.
 

taniaaust1

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These are probably proper ME patients - the CFS/ME Research Center is pretty much the only real ME center in the Netherlands that investigates and treats ME as presumptively biological. The lead researcher Ruud Vermeulen also has a good reputation in that regards (not be confused with Riem Vermuelen from the Academic Medical Center who equates ME/CFS with "medically unexplained symptoms" and psychosomatic illness).
thanks that is good to know.

Is till wonder thou if there still would be some selectial biased going on thou in that the worst affected patients just wouldnt do this... so one could say that is is a study of the less severely affected even if they are ME patients