Differentiating ME/CFS and FM re mitochondrial dysfunction

[MeSci]

I hope this isn't another duplication, but I can't find any threads in the latest ME/CFS research threads featuring the names of these researchers:

Could mitochondrial dysfunction be a differentiating marker between Chronic Fatigue Syndrome and Fibromyalgia?

Castro-Marrero J, Cordero MD, Saez-Francas N, Jimenez-Gutiérrez C, Aguilar-Montilla FJ, Aliste L, Alegre-Martin J.
Source

Vall de Hebron Univ Hospital Research Institute, CFS Unit, BARCELONA, Barcelona, Spain ; jesus.castro@vhir.org.
Abstract

Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are complex and serious illnesses. It is estimated to affects up to 2.5% and 5% of the general population worldwide, respectively. The aetiology is unknown; however, recent studies suggest that mitochondrial dysfunction has been involved in the pathophysiology of both conditions. We have investigated the possible association between mitochondrial biogenesis and oxidative stress in patients with CFS and FM. We studied 23 CFS patients, 20 FM patients and 15 healthy controls. Peripheral blood mononuclear cells (PBMC) showed decreased levels of CoQ10 from CFS patients (p<0.001 compared to controls) and FM subjects (p<0.001 compared to controls) and ATP levels for CFS patients (p<0.001 compared to controls) and for FM subjects (p<0.001 compared to controls). On the contrary, CFS/FM patients had significantly increased levels of lipid peroxidation, respectively (p<0.001 for both CFS and FM patients respect to controls) indicative of oxidative stress-induced damage. Mitochondrial citrate synthase activity was significantly lower in FM patients (p<0.001) and however, in CFS resulted in similar levels than controls. Mitochondrial DNA content (mtDNA/gDNA ratio) was normal in CFS and reduced in FM patients vs. healthy controls, respectively (p<0.001). Expression levels of PGC-1α and TFAM by immunoblotting showed significantly lower in FM patients (p<0.001) and were normal in CFS subjects compared to healthy controls. These data lead to the hypothesis that mitochondrial dysfunction-dependent events could be a marker of differentiation between CFS and FM indicating the mitochondria as a new potential therapeutic target for these conditions.

http://www.ncbi.nlm.nih.gov/pubmed/23600892

 

[Little Bluestem]

LIKE! LIKE! LIKE! I thought that I had mitochondrial/ATP cycle dysfunction long before I had any idea I had CFS.

 

[clive powney]

Sarah Myhill has been looking at this for 10 years

 

[Marco]

Hold on.

Both CFS and FM patients had low CoQ10 and ATP levels and raised levels of oxidative stress.

But only FM patients differed from controls on mitochondrial citrate synthase; mitochondrial DNA content and PGC1a (master regulator of mito activity) and TFAM (transcription factor) expression.

Sounds like mitochondrial problems are associated more with fibromyalgia.

 

[Little Bluestem]

That surprised me, too.

 

[MeSci]

Hold on.

Both CFS and FM patients had low CoQ10 and ATP levels and raised levels of oxidative stress.

But only FM patients differed from controls on mitochondrial citrate synthase; mitochondrial DNA content and PGC1a (master regulator of mito activity) and TFAM (transcription factor) expression.

Sounds like mitochondrial problems are associated more with fibromyalgia.

There is probably a wide range of possible mitochondrial abnormalities in various conditions. As Clive says, Dr Myhill has focused on mitochondria a lot, and this paper is interesting in terms of both evidence and theory:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403556/

 

[Mithriel]

ME has widespread, often severe pain as a primary symptom but when CFS was defined, although pain was included, it was not necessary and its presence often led to a co - diagnosis of fibro. I do not see how anyone nowadays differentiates between the pain of ME and the pain of fibromyalgia so I strongly suspect that many people with ME are being diagnosed as having fibro.

Research into the mitochondrial problems of ME was really going somewhere when CFS was invented and all that work was stopped.

In this present work CFS is most likely defined as fatigue while fibromyalgia is pain so the fibromyalgia patients may well actually have ME while the CFS patients, as usual, could have anything.

The usual diagnostic mess, in fact, leading to research that is wasted.

Mithriel

 

[MeSci]

I seem to be in a small minority of ME sufferers who get very little pain. I mainly just get muscle aches and usually-mild occasional abdominal pain. I do also get mild but nagging head-, neck- and upper-mid-back pain when my symptoms worsen, but rarely anything severe.

This suggests to me that either I have something else altogether (although everything else fits) or there are significant sub-groups, for which several researchers have found evidence.

 

[Mithriel]

I don't think it is sub groups, more different expressions of the disease. Ramsay said that the most obvious thing about ME was the variability of symptoms a patient experienced. You can go years without significant pain but then it suddenly becomes overwhelming or you can have sore feet in the morning, sore joints in the afternoon and then be unable to sleep because of muscle pain during the night.

It is like MS, the underlying physiological problem is what gives you the disease, not how that problem is expressed. That is why the best definitions, like the IC, are lists of possible symptoms and it is the overall pattern which determines if it is likely you have ME rather than something else (while we do not have any test for the underlying cause).

This is also the reason why it can be diagnosed within weeks and why people can have very mild symptoms most of the time but still have ME.

By contrast, CFS requires a certain severity of fatigue for a certain length of time.

I suspect that muscle aches are due to a build up of lactic acid so they will be mild if you are not damaging your muscles by your level of activity.

Mithriel

 

[Mya Symons]

This confuses me. If it the problem is mitochondria, then valcyclovir should probably make things worse. However, if I take valcyclovir, the involuntary muscle twitching is less. I am wondering if I don't take it at all for a long time if things will get better. Is it possible that some of us have some antibodies against mitochondria or something involved in the process of creating mitochondria?

 

[MeSci]

This confuses me. If it the problem is mitochondria, then valcyclovir should probably make things worse. However, if I take valcyclovir, the involuntary muscle twitching is less. I am wondering if I don't take it at all for a long time if things will get better. Is it possible that some of us have some antibodies against mitochondria or something involved in the process of creating mitochondria?

I wouldn't be at all surprised. There is a page about autoantibodies to mitochondria here:

http://www.nlm.nih.gov/medlineplus/ency/article/003529.htm

Interesting that it relates to primary biliary cirrhosis, which seems to have some common factors with ME and has come up in at least one recent thread.

 

[Mithriel]

My own illness has always felt as if it is a mitochondrial problem, but it began after a Coxsackie B infection, enteroviral, and was a sporadic case similar to the epidemics. The original research on mitochondria in the early eighties was most likely done on cases of enteroviral ME. As far as I know (I have not had much testing) I do not have any herpes viruses. It may be that actual ME, as seen in the epidemics, is not what everyone now has.

I have noticed over the years that glandular fever, mononucleosis, seems to have a different pattern of illness even though it is often thought of as the same as ME. It was a matter of great debate whether they were the same just before CFS was invented and everything went crazy.

Mithriel

 

[caledonia]

I don't have pain in general. However, if I stub my toe or something, I feel the pain 10 time worse than normal. Is this what you would call FM?

 

[Mithriel]

I get that with one of my fingers in particular, even a gentle tap feels as if I have trapped my finger in a door. Les Simpson in New Zealand found that the blood cells of his patients were deformed so that they could not get into the smallest veinlets easily and work by Vance Spence has also shown vasculitis. I think that is the best explanation.

At school, we had to play hockey when there was ice on the ground. If the ball hit the stick, frozen fingers were agony from the jolt so I always knew that less blood meant more pain

Work on FM has found suggestions that it is caused by the brain magnifying pain, or not damping it down, something like that. Of course, brain problems are rife in ME as well so that may not distinguish the two.

Mithriel

 

[alex3619]

The upshot of this, presuming it is right, is that both have high oxidative stress in the mitochondria, but FM has a problem with regulating mitochondrial function at the genetic level. Both are mitochondrial disorders, but they appear to be different types of mitochondrial disorders. This might explain why so many symptoms are similar in ME, CFS and FM.

I might be able to say more if I had the full paper. Abstracts are not always reliable, too much is brushed over.

Nerve cells are very vulnerable to mitochondrial disorders. Neurological issues are likely to follow.

In my case the worst muscle pain has nothing to do with lactic acid. Its about the muscle not repairing properly. Stretching muscle, even gently, can be as painful as heavy exercise if the muscle has been aggravated - and does not recover quickly. It took me about twenty years to recover from the pains I had in the 80s. I am not sure if its even muscle, but rather vascular or myofascial sheath issues ... connective tissue. Now this might be because something about whatever is causing elevated lactate or even alkaline muscle at rest is damaging repair, or muscle is failing to repair, or that I have undiagnosed (and not hypermobile) EDS.

 

[Mithriel]

FM was never associated with ME. ME had a problem with exercise, what we would call PEM, as its cardinal symptom with pain a close second. I was told by a doctor that when he was at the Royal Free during the epidemic the patients would hit the roof when they were touched. A deep burning pain, presumably from lactic acid build up is common and indicates a problem with mitochondrial function which research was beginning to work out.

Then came CFS. The research money went to AIDS, and, especially in the UK, the psyches took over. When I first heard of FM, about then, very gentle exercise was seen as giving the best relief, though many people still needed strong pain killers.

However, as the confusion started, people with CFS but a lot of pain started being told they had FM as well. I believe that this was an artefact of the fact that CFS was so loosely defined and ME with its emphasis on exercise problems, was forgotten.

After decades of this diagnostic confusion, I do not think it is possible to do a meaningful study differentiating FM and CFS because there are no pure samples of patients. If PEM is not taken into consideration, patients with widespread pain are just as likely to have ME not FM and since ME does not need fatigue - I have never experienced 6 months of constant fatigue, rather I experience a collapse after effort, but that is not what the definition of CFS actually says - the CFS group may contain very few people with ME. This is especially insidious since neurological signs are exclusionary to CFS and in some studies this has included a positive Romberg sign which is almost diagnostic of ME!

Until we have very strict research definitions (diagnostic definitions can be much looser) all the research is little better than astrology.

It makes me very angry.

I have not been posting to forums for a while and thought I was well enough to start again but it has not been as easy as I hoped. If I do not reply, it is simply my health and I wish you all well and still hope for a time when we are given the research, respect and consideration we deserve.

Good health to everyone

Mithriel

 

[alex3619]

The problem with definitions is still we do not know what it is we are defining. We need reliable biomarkers, and the lack of those is a failure in research and research funding - a lack of political will. With all the cluster outbreaks there have been, we have missed many many opportunities to study pure patient populations. The only pure populations that exist are the cluster outbreaks, such as the Royal Free Hospital outbreak. However even then we cannot be sure that each cluster outbreak is the same disease.

It is not impossible to define population subgroups in CFS etc. but that requires very large funding, large numbers of patients, and ongoing investigations. We have never had that level of committment from any funding agency or researchers. Such subgroups should, if done adequately, include one or more that matches the ME cluster outbreaks. Instead we have lots of research going the other way in the UK and Europe - generalize to absurdity (the Oxford Definition, but similar issues might have occured with CDC attempts), then claim there is anything that can be inferred from such a massively heterogenous group.

I have serious doubts the CDC will do this, but I can still hope.

Now it is correct to say that if we started with, for example. Ramsay defined ME then the search would be cheaper and easier, and probably quicker. The definition of CFS and its broadening without justification (again, Oxford) has never been validated and is of dubious reliability at best. However we cannot be sure that Ramsay is much better, and its certainly complicated with psychobabble aspersions - it was the Royal Free Hospital outbreak that, fifteen years later, led to a paper that claimed all ME is hysteria.

 

[Enid]

I haven't studied the various attempts to "define" ME (nor CFS/FM) having viewed the original ME Canadian Consensus and agreeing entirely. Whilst some of the symptoms listed may have waxed or waned, they came/were there at one time or another, some never improving. Would personally suggest the worst case scenario - those severely affected would make the best study for ME (and more) - those criteria/pathologies listed and cause found because I think CFS/FM lie on the same continuum.

 

[alex3619]

Enid, case severity is a whole other issue. Very few studies (two?) have studied patients at the worst end of illness severity. I agree that they would be a better group to study than mild patients (I suspect they would have more obvious abnormalities, while typically being those least investigated by treating doctors?) but any results from mild patients (which is what most studies look at) cannot be reliably extrapolated to these severe patients. They are at once the most deserving as patients and the most forgotten in research.

 

[Enid]

Alex. I appreciate your point here but some extrapolation in the reverse could apply - that is ME severe sufferers share symptoms with CFS and FM. "Crack" that one might reveal more of the origins/pathogenesis of what is termed CFS (about time they dropped that title) and FM. Though I appreciate the severity of "severe" can make any study difficult.

(Hope your break is healing well now).