Loss Of Capacity To Recover From Acidosis On Repeat Exercise In CFS (Jones et al,'11)

Dolphin · Jun 30, 2011

Loss Of Capacity To Recover From Acidosis On Repeat Exercise In Chronic Fatigue Syndrome A Case Control Study

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2011.02567.x/abstract

LOSS OF CAPACITY TO RECOVER FROM ACIDOSIS ON REPEAT EXERCISE IN CHRONIC FATIGUE SYNDROME A CASE CONTROL STUDY

David EJ Jones MD PhD1,, Kieren G Hollingsworth PhD1,2,, Djordje G Jakovljevic PhD3,4,5, Gulnar Fattakhova MD3,4, Jessie Pairman3,4, Andrew M Blamire PhD1,2, Michael I Trenell PhD1,4,5,, Julia L Newton MD PhD3,4,

European Journal of Clinical Investigation 2011 DOI:
10.1111/j.1365-2362.2011.02567.x

Author Information
1Institute of Cellular Medicine
2Newcastle Magnetic Resonance Centre
3Institute for Ageing and Health
4the UK NIHR Biomedical Research Centre in Ageing and Age Related Diseases 5Newcastle Centre for Brain Ageing and Vitality. Newcastle University, UK

*Correspondence: Professor Julia L Newton Institute for Ageing and Health Medical School Framlington Place Newcastle-upon-Tyne NE2 4HH, UK Tel: 0191 2824128 Email: j.l.newton@ncl.ac.uk

Abstract*

Background:?

Chronic fatigue syndrome (CFS) patients frequently describe difficulties with repeat exercise.

Here we explore muscle bioenergetic function in response to 3 bouts of exercise.

Methods:?

18 CFS (CDC 1994) patients and 12 sedentary controls underwent assessment of maximal voluntary contraction (MVC), repeat exercise with magnetic resonance spectroscopy and cardio-respiratory fitness test to determine anaerobic threshold.

Results:?

CFS patients undertaking MVC fell into 2 distinct groups. 8 (45%) showed normal PCr depletion in response to exercise at 35% of MVC (PCr depletion >33%; lower 95% CI for controls).

10 CFS patients had low PCr depletion (generating abnormally low MVC values).

The CFS whole group exhibited significantly reduced anaerobic threshold, heart rate, VO2, VO2 peak and peak work compared to controls.

Resting muscle pH was similar in controls and both CFS patient groups.

However, the CFS group achieving normal PCr depletion values showed increased intra-muscular acidosis compared to controls after similar work after each of the 3 exercise periods with no apparent reduction in acidosis with repeat exercise of the type reported in normal subjects.

This CFS group also exhibited significant prolongation (almost 4-fold) of the time taken for pH to recover to baseline.

Conclusion:?

When exercising to comparable levels to normal controls CFS patients exhibit profound abnormality in bioenergetic function and response to it.

Although exercise intervention is the logical treatment for patients showing acidosis any trial must exclude subjects who do not initiate exercise as they will not benefit.

This potentially explains previous mixed results in CFS exercise trials.

* I've made each sentence its own paragraph

Dolphin · Jun 30, 2011

Basically, this found it was useful to divide the CFS patients into two groups: those who seemed to have done a "proper" (my words) exercise test and those that didn't.

When the groups were divided up in this way, those who did a proper exercise test had abnormal results while those that didn't do a proper exercise test, did not have abnormal test results.

Unfortunately a lot of the focus is on the group who didn't do a proper exercise test; there is less talk about the group with the abnormal results which is the more interesting group in my mind.

Dolphin · Jun 30, 2011

Heterogeneity

The authors make points about heterogeneity. However, I think they have simplified it too much - I think that simply dividing patients up between those who did the exercise test sufficiently and those that didn't isn't proper heterogeneity and may not be sufficient to explain the results in the literature (e.g. Lane et al., 2003 found that the presence of enterovirus in the tissue was useful).

Previous studies have confirmed the presence of two muscle phenotypic groups within the those patients fulfilling the diagnostic criteria for CFS [15]. A previous MR study performed at the forearm and not involving repeat exercise bouts suggested that abnormal lactate responses to exercise and MRS characteristics of excessive acidosis were consistent with impaired capacity for mitochondrial ATP synthesis [15] in CFS, although again significant inter-patient variability was seen.

Our findings do, however, have an important implication for studies of muscle function and exercise therapy in CFS. If replicated and found to be generalisable they suggest that such studies, if undertaken without some form of exercise bioenergetic screening such as achievement of a threshold level of PCr depletion following exercise at a fixed percentage of objectively assessed MVC, will include subjects who may not undertake the requisite levels of physical activity without some form of additional behaviour-changing intervention. Our findings suggest that MR-directed stratification strategies would represent a potentially important tool in future studies of exercise and exercise therapy in CFS. The absence of such stratification, and the inclusion of exercise-avoiding patients in previous studies and trials may go some way to explain
variability in findings and therapeutic efficacy.

We believe our current study adds further confirmation to the concept of CFS as complex and heterogenous disease (I don't think this study shows much about it being a heterogenous disease - it found one group which had an abnormal response after an exercise test and another group who didn't seem to try hard enough on the exercise test - that's not proper heterogeneity in my book - we don't know what the second group would have been like if they had exercise fully - everyone could have had the same response). We would suggest that it is inappropriate to draw conclusions (frequently negative) concerning the aetiology or pathogenesis of CFS from investigations conducted on broad cross sections of poorly characterised patients. To fully understand the peripheral muscle abnormalities in those with a diagnosis of CFS it is becoming increasingly vital to characterise patients using a wide range of assessments including the state of the art MR technologies described in our study. We believe that it is only when this approach is taken, as was the case in this study, that specific mechanisms at play in different patient groups will be identified and that we will make progress towards what is surely needed; a stratified and targeted approach to treatment in CFS.

Dolphin · Jun 30, 2011

How the CFS group was divided into two groups

Maximum voluntary contraction in the CFS group compared to controls

The CFS patients as a group also had significantly lower maximum voluntary contraction values compared to the controls but with a markedly larger value spread (Figure 2a).

In order to explore the basis of this effect we went on to look at bioenergetic function using MRS when subjects exercised at a fixed percentage of their MVC (35%). When the sedentary normal controls were assessed to determine their MVC, and then undertook repeat exercise at 35% of that MVC, a consistent pattern of phospho-creatine (PCr) depletion was seen across their initial exercise episode (40% depletion 13%, 95%CI 33-47%). We used the lower 95% CI value for PCr depletion in response to exercise at 35% of MVC (33%) to define a cut-off for normal exercise bioenergetic impact (PCr depletion >33%) and low exercise bioenergetic impact (PCr depletion <33%) for exercise at 35% of MVC for the time period used in our study protocol. In contrast to the sedentary normal controls, the CFS patients undertaking exercise at 35% of their individually determined MVC exhibited a wide range of PCr fractional depletion spanning from almost zero to within normal control levels. Using our definitions of normal and low PCr depletion, 8 CFS patients (45% of the study cohort) fell into the normal group and 10 (55%) fell into the low PCr depletion group. The sub-normal levels of PCr fractional depletion seen in the low group appeared to be a consequence of MVC being significantly lower than in either the control population or the normal PCr depletion CFS patients (whose MVCs were identical to the control population) (Figure 2b). Within the CFS population, therefore, there is a subgroup who, in the context of a formal assessment protocol exhibit a normal maximum voluntary contraction, and who subsequently show proportionate PCr depletion when exercised at 35% of that MVC. There is also, however, a second subgroup of CFS patients who, when undertaking the same assessment protocol exhibit a significantly lowered level of maximum voluntary contraction and, subsequently, proportionately lower PCr depletion on exercise. This finding suggests that where low MVC is seen in CFS patients it is not a consequence of impaired capacity to do exercise (in which scenario low MVC might be expected to give rise to a normal level of PCr depletion) but a reduced drive to exercise.

(Note: when one sees Figure 2b, one can see there is a bit of variety within the two groups).

The authors spend more of the paper talking about the low PCr group depletion group than the other group; a lot of this is speculative in my mind. Also, I don't think one can extrapolate from which people may respond to an exercise test to say that one knows who will and won't stick to a GET program, where the exercise is a lot different to these lab tests.

Dolphin · Jun 30, 2011

The CFS group with an abnormal pH response

Given it's not an open access article, I can only post so much of the paper. I find the CFS group with an abnormal pH response more interesting so going to concentrate on what is discussed regarding them.

We observed that CFS patients as a group have reduced cardio-respiratory reserve with a lower anaerobic threshold than sedentary controls. This finding replicates previous studies [3]. One implication of a lowered anaerobic threshold would be increased reliance on anaerobic as opposed to aerobic metabolism with a predicted consequence of increased short term acid generation within muscle due to over-utilization of the lactate dehydrogenase pathway. This prediction was confirmed by the use of MR spectroscopy methodologies which demonstrated increased post-exercise acidosis in the CFS group as a whole. The effect was not, however, uniform across the CFS patient group.

In the CFS subjects where normal PCr depletion was seen in the context of a normal MVC, exercise induced profound and sustained acidosis. This replicates our previous findings [18] in a second cohort of patients with CFS. Importantly, minimum pH values attained by this group of CFS patents were actually lower than those previously shown by us in the fatigue-associated chronic disease primary biliary cirrhosis (PBC) [28]. We would suggest that the increased reliance upon anaerobic metabolism during even relatively lowlevel muscle contraction, shown by a decreased intramuscular pH, is at least partly a consequence of the decreased aerobic capacity (reduced anaerobic threshold and VO2peak) seen in CFS, and in this regard the physiology of fatigue in CFS closely mirrors that in PBC.

There are aspects of the abnormality in acid homeostasis in CFS which differ to those seen in PBC and which may significantly contribute to the severity of fatigue in CFS. We have previously reported that when PBC patients undergo repeat exercise the degree of acidosis seen within muscle reduces with each exercise episode, suggesting the retention of some compensatory capacity for excess muscle acidosis in PBC (28). One mechanism for this is increase in proton flux, and the speed of onset of maximum proton excretion, with repeat exercise. This phenomenon, which is also a feature of mitochondrial disease where increased proton efflux after exercise helps compensate for reduced aerobic capacity [35], was absent from the CFS patients. These findings suggest that CFS patients are unable to compensate for the increased reliance upon anaerobic energy sources during muscle contraction in comparison to other conditions with reduced aerobic capacity. The net effect of these combined effects can be seen in terms of cumulative acid exposure determined from the area under the curve for pH. Using this approach total post-exercise acid exposure is of the order of 50-fold higher in CFS patients exercising to the same degree as normal controls, with no reduction in this pattern of sustained high level acidosis with repeat exercise. We believe that the local and systemic sequelae of this sustained acid exposure contribute significantly to the expression of fatigue in CFS.

The reasons for slowed recovery from muscle acidosis in CFS are at present unclear but there are a number of possibilities. Our finding of a slow recovery time appears to be at least in part a result of slow kinetics of proton excretion and may point to potential mechanisms by which the increased muscle acid exposure occurs. Acid is actively transported from the muscle by Na-H antiporters which are in turn under autonomic regulation. Indeed, conditions which increase sympathetic tone such, as hypertension [36], or following sympathetic denervation [37] change acid handling in muscle. It is possible that impaired function of acid transporters occurs in CFS and that this related to the autonomic dysfunction found frequently in those with CFS [2, 19-22]. It is also possible that reduced vascular run off (related to autonomic dysregulation) may also contribute. Furtherwork is needed to explore the underlying mechanisms fully. Importantly, many of the pathways for acid excretion from muscle cells can be upregulated by exercise therapy suggesting a possible mechanism for benefit with graded exercise therapy (although our caveats about stratification should be noted).

I think the talk about graded exercise therapy is speculative and may be influenced by the NICE guidelines and the culture in the NHS. They may also think the previous trials have been more successful than they really have been. In the introduction, they mention:

The recently published PACE trial [14] suggests that some patients with CFS may benefit from structured exercise programmes, however our ability to identify those who would benefit from exercise therapy aimed at improving physical capacity (and importantly those who would not) is currently limited.

This controversy in the literature relating to muscle performance abnormality in CFS, and thus the potential benefit of exercise therapy, is difficult to resolve and may relate to patient selection in different studies, the presence of different phenotypes within the diagnostic category of CFS [15] or because patients may have variable difficulty making or sustaining maximal effort [4,16] because of the perceived consequences [17].

End (which also covers the other CFS group):

This study has a number of limitations. Although we present positive findings we acknowledge that the numbers of patients studied are small and that replicative studies performed in other centres are needed. In future studies we would also wish to include validated quantitative measures of post exertional malaise, pain and kinesophobia in order to better guage the impact and influence of these symptoms. This study has examined the relationship between muscle function and symptoms, however it is important to acknowledge that we did not explore other potential factors that might lead to post exertional malaise such as central feedback [38,39] or immune dysregulation post exercise [40] or abnormalities of muscle fibre types. Future studies need to consider the relationships with these parameters and muscle bioenergetic function.

A large group of CFS patients consciously or sub-consciously do not exercise when invited to and do not show bioenergetic abnormality as a result. Although exercise intervention is the logical treatment for the patients showing acidosis future trials must exclude those subjects who do not initiate exercise as they will not benefit. Failure to do so potentially explains previous mixed results in CFS exercise trials.

I'm presuming they're saying it's "logical" because of what happens with other groups with regard to acidosis - but the same effect wasn't found with the CFS patients (repeating a quote from above):

We have previously reported that when PBC patients undergo repeat exercise the degree of acidosis seen within muscle reduces with each exercise episode, suggesting the retention of some compensatory capacity for excess muscle acidosis in PBC (28). One mechanism for this is increase in proton flux, and the speed of onset of maximum proton excretion, with repeat exercise. This phenomenon, which is also a feature of mitochondrial disease where increased proton efflux after exercise helps compensate for reduced aerobic capacity [35], was absent from the CFS patients.

Dolphin · Jun 30, 2011

Light study and this study

Using this approach total post-exercise acid exposure is of the order of 50-fold higher in CFS patients exercising to the same degree as normal controls, with no reduction in this pattern of sustained high level acidosis with repeat exercise. We believe that the local and systemic sequelae of this sustained acid exposure contribute significantly to the expression of fatigue in CFS.

I think the Lights should take this finding on board when they find increased acid sensors - that it's most likely because there's increased acid!

justinreilly · Jun 30, 2011

As in many of these ridiculous papers, they find actual physical pathology and then in the conclusion warp it some way to suggest GET and/or psychogenesis.

The last two sentences are very troubling to me. It says that ME should be treated with 'exercise intervention' (GET) because this is the proper treatment for acidosis. Also says that pw"CFS" who do not normally exercise should be excluded from any study because they may not comply with the GET instructions and thus artificially lower the measured effectiveness of GET in trials like PACE. Obviously, if pw-Oxford defined "CFS" who normally exercise are studied, all of the people in the study will have Idiopathic Chronic Fatigue not ME.

Sean · Jun 30, 2011

Nice one, Mr D. Thanks for that.

"18 CFS (CDC 1994) patients and 12 sedentary controls..."

I do love a well controlled study to go with my morning coffee.

Sean · Jun 30, 2011

Have to admit it is not entirely clear to me what they mean here:

A large group of CFS patients consciously or sub-consciously do not exercise when invited to and do not show bioenergetic abnormality as a result. Although exercise intervention is the logical treatment for the patients showing acidosis future trials must exclude those subjects who do not initiate exercise as they will not benefit.

SilverbladeTE · Jun 30, 2011

justinreilly said:
As in many of these ridiculous papers, they find actual physical pathology and then in the conclusion warp it some way to suggest GET and/or psychogenesis.

The last two sentences are very troubling to me. It says that ME should be treated with 'exercise intervention' (GET) because this is the proper treatment for acidosis. Also says that pw"CFS" who do not normally exercise should be excluded from any study because they may not comply with the GET instructions and thus artificially lower the measured effectiveness of GET in trials like PACE. Obviously, if pw-Oxford defined "CFS" who normally exercise are studied, all of the people in the study will have Idiopathic Chronic Fatigue not ME.

Sorry but the obvious bias in weighting conclusions is like a direct historical repeat of research that got skewed to show non-whites, specific minorities, women, or whatever group were "subnormal", "malingerers" or whatever crap the bigots wanted :/
They are projecting their bias, which is utterly outrageous and unscientific.

if someone's so sick they can't do much exercise, well DUH! Maybe it's 'cause they are sick, and the ones who say otherwise are the ones who are sick in the head
Hey maybe they should see if the bumps on our head have any relevance to it all! yes, let's go back to the wonderful wonderful science of Phrenology! Just as valid as Psychiatry and gets you a free head massage too boot! :innocent1:

"Der good ver nothink ME/CFS patients vould not do ze 3 mile swim through ze shark infested vaters so our tests didn't vork, proving zey are lazy undermensch vho should be shot!"

Dolphin · Jun 30, 2011

Sean said:
Have to admit it is not entirely clear to me what they mean here:

A large group of CFS patients consciously or sub-consciously do not exercise when invited to and do not show bioenergetic abnormality as a result. Although exercise intervention is the logical treatment for the patients showing acidosis future trials must exclude those subjects who do not initiate exercise as they will not benefit.

Click to expand...

It's nothing too deep.

Basically their theory is that some people are so phobic about exercise that they won't do an exercise program; and the ones that do exercise have excess acidosis which they claim has a logical treatment, exercise.

As well as the reasons given above, I think part of their reasoning is that the patients get the acid from exercise in the anaerobic phase - if one can get people fitter so they don't hit the anaerobic phase, they won't experience the acid as much (I think that is what they are saying/hinting at) as well as (what I said previously that) they're extrapolating from other groups, where doing exercise may reduce excessive acidosis (but they haven't shown it works in CFS and indeed, their results suggests the opposite happens in CFS to other groups).

Kati · Jun 30, 2011

I am interested to this article because when I had my 2 days VO2 max test, I was already in acidosis BEFORE starting the test. The next morning, after the first test, my ratio CO2-O2 was still very high and I was discouraged from doing the second test.

I don't have access to the article, not that my brain could understand it all right now anyways...

But I wanted to mention that athletes use "active rest" as a way to flush out the lactic acid from their muscles. Cyclists will go ride slowly, with lower gears, for a much shorter ride.

Exercise physiologists in the like of Staci Stevens or Connie Sol (Miami) will recommend short duration- light exercice like stationary bike or walk at a heart rate lower than your own anaerobic threshold. For some, it may just mean walking to the mailbox and back, or to the washroom and back. And I do not think it is meant to be a curative regimen. Progress is likely measured in months rather than days.

My 2 cents.

Snow Leopard · Jul 1, 2011

Thanks for your analysis Dolphin.

Sean · Jul 1, 2011

Thanks for that explanation, Dolphin.

oceanblue · Jul 1, 2011

Isn't this study a tad on the small size? 18 patients would on the small size for a well-defined disease but for a heterogenous illness like CFS it's very small. By the time you've split the patients into 2 sub-groups the numbers become tiny. And just 12 controls? I'd be interested to know how well matched they were to the patients. Using the PCr levels from such a small group to establish a 'normal' threshold against which to measure patients is suspect, particularly if they were not well matched.

Dolphin said:
The authors spend more of the paper talking about the low PCr group depletion group than the group; a lot of this is speculative in my mind. Also, I don't think one can extrapolate from who people may respond to an exercise test to say that one knows who will and won't stick to a GET program, where the exercise is a lot different to these lab tests.

As I understand it, the difference stems from the one CFS group 'not trying hard enough' at the Maximal Voluntary Contraction test. As dolphin says, this is speculation. To spell things out re different exercise test, MVC is a) anaerobic and b) maximal, neither of which apply to Graded Exercise, concluding that you can use MVC to predict willingness to exercise in GET is a little wishful.

Dolphin · Jul 1, 2011

oceanblue said:
Isn't this study a tad on the small size? 18 patients would on the small size for a well-defined disease but for a heterogenous illness like CFS it's very small. By the time you've split the patients into 2 sub-groups the numbers become tiny.

My guess is that they didn't necessarily plan to have two groups of CFS patients but noticed there was a division in the amount of acid and investigated.

oceanblue said:
And just 12 controls? I'd be interested to know how well matched they were to the patients.

oceanblue · Jul 1, 2011

Dolphin said:
My guess is that they didn't necessarily plan to have two groups of CFS patients but noticed there was a division in the amount of acid and investigated.

But if you start off with such a hopelessly small sample you have nowhere to go if there are any problems along the way, such as the one they found.

I see the 'sedentary' controls were defined as 'less than 30mins exercise 3 times a week', which isn't really very sedentary - the recent Suarez study on nitric oxide that you posted made a much better job of selecting sedentary controls. Basically that's 12 poorly-matched controls.

Dolphin · Jul 1, 2011

oceanblue said:
But if you start off with such a hopelessly small sample you have nowhere to go if there are any problems along the way, such as the one they found.

Yes; if more money was raised for research by the ME/CFS community, etc. I'm sure they, like most researchers, would love to use bigger sample sizes.

oceanblue said:
I see the 'sedentary' controls were defined as 'less than 30mins exercise 3 times a week', which isn't really very sedentary - the recent Suarez study on nitric oxide that you posted made a much better job of selecting sedentary controls. Basically that's 12 poorly-matched controls.

Yes, not good definition of sedentary.

Glynis Steele · Jul 1, 2011

I don't know whether this is relevant to this thread, but it has been noted that when d-lactic acid and l-lactic acid are found in high amounts, they will cross inhibit each other's metabolism.

However, when D- and L-lactic acids are present in high concentration they will cross inhibit each other's metabolism. D-lactic acidosis results from its over-production and accumulation.

.

From this paper http://hkjpaed.org/details.asp?id=577&show=1234

D-lactic acid producing bacteria were found in higher than normal level's in the Sheedy paper, in CFS patients.

http://www.ncbi.nlm.nih.gov/pubmed/19567398

Glynis x

Purple · Jul 1, 2011

Firstly, my observation from Table 1 posted above by Dolphin is the relatively high BMI of 27/28. Is that typical of ME/CFS? (is there any literature on this?)

Secondly, what is the 'Fatigue Impact Scale' referred to?

Loss Of Capacity To Recover From Acidosis On Repeat Exercise In CFS (Jones et al,'11)

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