Researchers are finally starting to look at what is probably the key problem in CFS – an inability to ‘exercise’ without relapsing. Following the publication of a Pacific Fatigue Lab paper which suggested that a reduced ability to produce energy following exercise might be at the core of the post-exertional relapse (PER) problems in CFS researchers have begun to focus more on exercise and stress testing.
2010 indicated that this subject has taken hold in the small ME/CFS research community.
First we take a look at validation studies – a key, key issue for any ME/CFS topic. Can researchers using a population that is presumably filled with subsets validat the original findings? Then we look at what researchers are doing to figure out why these problems are present and what might be causing them.
Validation
The Core Biological findings
Quick Drop in Exercise Tolerance in Adolescents after ME/CFS – Dr. Taylor is rolling out papers from her big NIH-funded infectious mononucleosis study. In this study she shows that adolescents that come down with ME/CFS during infectious mononucleosis quickly see their exercise capacity drop markedly. They were still able to engage in normal levels of ‘peak work capacity’ but had significantly lower peak oxygen consumption – a finding commonly found in older patients with longer duration of their illness. This paper indicated that the energy production problems in ME/CFS occur early in the illness. While it didn’t pave much new ground it hopefully laid the groundwork for a deeper exploration of exercise and ME/CFS.
Symptom Exacerbation
This Pacific Fatigue Lab study found that only 1 of 25 female CFS patients recovered from a maximal exercise test 48 hours later while all 23 sedentary controls did. Symptoms experienced by the people with ME/CFS included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands.
The Pain of it All – A Belgium study looking at pain and exercise followed shortly. The Van Oosterwiick/Nijs study found that pain thresholds – the amount of pressure needed to induce feelings of pain – decreased sharply in people with CFS but increased in healthy controls. Essentially the healthy controls were less sensitive to pain after exercise while the people were ME/CFS were more sensitive to pain.
Another Belgium study from Meesus looked at pain thresholds in people with lower back pain (which sometimes is fit into a somatic category), people with ME/CFS and healthy controls after exercise and found that people with ME/CFS had lower pain thresholds (i.e. experienced more pain) after submaximal exercise than either low back pain patients or healthy controls. This indicates that the process of pain induction in ME/CFS is different from that in this other possibly ‘psychosomatic group’.
‘Central’ Pain Processing Issues – Both researchers referred to ‘central’, i.e. central nervous system, pain processing problems. Although they don’t suggest why exercise would activate pain-enhancing CNS pathways and/or inhibit the pain inhibiting processes in people with ME/CFS, they document a decidedly abnormal finding – which, in its own way, is as anomalous as the Pacific Fatigue Lab’s findings of reduced aerobic capacity after exercise. Studies after all show that when healthy people exercise they become less sensitive to pain; the finding that people with ME/CFS are more sensitive is a directly opposite to the expected response. While that’s not a new discovery for people with ME/CFS, academic support of that fact is critical.
These findings may connect the pain sensitization processes found in fibromyalgia with similar findings in ME/CFS.
There are surely enough overlaps between the two disorders to warrant an ME/CFS/FM(GWS/IBS?) International workshop. Despite the close connections between the two disorders, FM and ME/CFS researchers rarely work together. At the last OFFER conference FM, Dr. Wood noted with surprise how much he had learned from the ME/CFS talks. This is a ripe area for collaboration and investigation.
Biology – Looking for the Cause of the Post exertional Relapse (PER) experienced in CFS
Some things (RNase L, lactic acid buildup, reconditioning, and catastrophizing) have pretty much been ruled out. Some of the other possibilities include complement activation, cytokine upregulation, mitochondrial abnormalities, muscle receptor upregulation, gut changes, autonomic nervous system problems, increased oxidative stress at the muscle level, blood vessel problems, poor ‘planning processes’ in the brain, reduced muscle activation, enteroviral activation – and probably quite a few more.
Strike out in Belgium – The busy Belgium group lead by Nijs struck out when they looked at some suspected immune components following exercise. Neither elastase (an important vascular enzyme implicated in earlier studies in CFS) nor IL-beta nor, rather painfully, complement C4a, an immune factor identified in prior exercises studies in ME/CFS, were altered in ME/CFS patients following a submaximal exercise test.
A Strong Possibility Explored – Next, UK researchers funded by Meruk looked at the IL-6 cytokine levels during exercise. There are a number of really good reasons to think IL-6 might be involved in the post-exertional malaise experienced in ME/CFS. It’s actually produced from muscles and becomes elevated when muscles contract and, not surprisingly, IL-6 levels go up significantly during exercise. It is also produced by the smooth muscle cells that line the blood vessels – an interesting point given the possible vascular problems in CFS. Since it has pro-inflammatory characteristics it could contribute to the pain and flu-like feelings experienced in ME/CFS and it actually upregulates IL-10, a cytokine that has been shown to be elevated in ME/CFS studies. Plus, Il-6 levels go up in response to muscle damage.
In short, IL-6 seems like the perfect cytokine for PER but, even though these researchers looked for both it and its receptors, they were unable to find any differences between controls and ME/CFS patients before or after a submaximal exercise test. Important oxidative stress products called F2 Isoprostanes were significantly increased in ME/CFS both before and after exercise – thus validating prior study results.
Light on the Exercise Issue – Just three months later, though, the Light team in Salt Lake City, Utah, weighed in with another cytokine study; after a submaximal exercise effort they found, well, cytokine levels (including IL-6) to have been raised in at least one CFS group.
The Light group (which included Dr. Bateman, who is very interested in the subset issue) took a deeper dig at the patient cohort and found that separating them into high ‘symptom flare’ (high PEM) and low ‘symptom flare’ (more exercise tolerant) groups revealed remarkable differences. The ‘wiped out by exercise’ group had significantly higher levels of IL-1B, IL-12, IL-6, IL-8, IL-10 and IL-13 8 hours after exercise (but apparently not 24 and 48 hours later). The low symptom flare group had comparatively lower IL-10, IL-13 and CD-40L.
Interjection – We know that cytokines can cause many of the symptoms in ME/CFS and one of the Dubbo studies suggested that cytokine upregulation could trigger more problems in people with ME/CFS (in fact, could trigger the disorder) than in people without it. This idea – that relatively normal (or at least not exceedingly abnormal) cytokine levels could trigger an abnormal response – is a tough one for researchers to get at. The first Light study – with its finding of receptor upregulation, however, provides a way to explain that process. In the Light scenario, cytokines or lactic acid or other substances don’t need to be increased very much to cause problems if the receptors looking for them are on especially high alert – and thus respond overly strongly to the smallest upticks. If this is correct, then CFS is more a problem of improper communication (signaling) between the body and the brain.
That said, Light did find significantly higher cytokine levels in people with ME/CFS following exercise. Pairing that up with an overly-active signaling system would seem to be a recipe for problems.
This study suggests how important it is to examine subsets of patients based on symptoms or whatever other parameters are available. It’s astonishing how, after all the talk about subsets for decades, few researchers try to account for them. The Light group is looking at subsets in their receptor findings as well and are reportedly surprised at what they’ve found. Here we see what a dramatic difference doing so might be able to make.
A New Possibility Emerges – The Suarez Spanish group didn’t dally around with a submaximal exercise test; instead they pushed their participants to the limit with a maximal exercise test. This interesting study didn’t find any increases in glucose or lactate but they did find increases in nitrates – and not small differences either; they were large enough (300% higher) to warrant a p>.0001 figure, far more than needed to reach ‘significance’ in a research study (typically p<.05). Interestingly, the nitrate levels at baseline were normal in both groups and then went up in the people with CFS when they exercised.
This is a fascinating finding. Nitric oxide produced by the blood vessels (eNOS) is a vasodilator – it opens up blood vessels to allow for more blood flow – which is generally thought of as a very good thing; physicians, after all, use nitroglycerin and another nitrates to increase NO levels and blood flows in their heart patients. This type of NO production, which is prompted by the endothelial tissues in blood vessels in response to increased blood flow through them, is entirely appropriate.
But high NO levels in ME/CFS could conceivably reflect a very different process of NO formation. High free radicals (ie the F2 Isoprostanes in the MERUK study) or pro-inflammatory cytokines (e.g. Light) in the blood can trigger the iNOS enzyme to produce very high levels of NO. Maes, in fact, has found that high levels of the ‘bad’ nitric oxide enzyme (iNOS) correlated with increased cytokines in CFS patients. These high NO levels can then contribute to the production of free radicals (e.g. peroxynitrate) that can damage the mitochondria.
The high findings suggest that, instead of opening blood vessels, the NO in CFS patients is producing free radicals that could possibly shut down the mitochondria. The rise in nitrate levels during exercise suggests that an inflammatory reaction is driving this process – although its cause is still unclear. This study also validated the reduction in VO2 max found in the Pacific Fatigue Lab study.
Inflammation, immune activation, validation of the VO2 max findings …this was an informative study.
The main result of the present study is that nitric oxide (NO) metabolites (nitrates) showed a much higher increase after a maximal physical test in CFS patients than in a group of matched subjects. This combination (exercise plus NO response evaluation) may be useful in the assessment of CFS. https://pubmed.ncbi.nlm.nih.gov/20469961
The Spanish findings of very nitrate levels in the blood suggest that immune activation or oxidative stress could be triggering the production of an enzyme (iNos) that accelerated the process enough to damage the mitochondria.
Mitochondria Or Something Else?– The Dutch Vermoulen exercise study examined whether mitochondrial problems were causing the poor energy production in ME/CFS. After validating the core findings of reduced energy production during exercise Vermoulen examined rates of ATP synthesis in an exercise-to-exhaustion study involving people with ME/CFS and healthy controls.
They were unable to find evidence that the ATP production process itself was inhibited in ME/CFS. Instead, their findings suggested that reduced oxygen delivery to the tissues was causing the reduced energy production in ME/CFS; simply put, either reduced blood flows to the muscles or impaired oxygen delivery from the blood was preventing oxygen – the key ingredient in our aerobic energy system – to make it to the mitochondria in the muscles.
An Entirely Different Cut – The Jones/Newton UK study took an entirely different cut at the problem. Instead of engaging in a full body aerobic energy study, they simply had the participants flex their lower leg muscles in a submaximal energy test and then used an MRS scan to measure ph levels (i.e. the acid buildup that occurs during anerobic respiration) and how well the muscles were getting rid of the protons (hydrogen ions).
They found that pH levels were not different in people with ME/CFS and healthy controls during this short 3 minute test but that ‘proton efflux’ was. In healthy controls, as the pH levels rose the muscle cells began pumping the excessive protons (hydrogen ions) out of the muscles and into the blood. Immediately after exercise there was no indication that this was happening in muscles of the ME/CFS patients. (Note the authors are using CFS/ME in the quote below)
This, of course suggests some sort of metabolic breakdown was occurring. Interestingly enough, it did not appear to be in the mitochondria; once again, other testing suggested that mitochondrial functioning was normal, which, as the authors noted, has now been found in six studies.
After characterizing the problem, they looked for a possible reason for it – altered autonomic nervous system (ANS) functioning – and found it. That they did was no surprise, really; the heart rate variability test they used has about as consistent results as oxidative stress results – they are almost always abnormal.
But how does autonomic nervous system (ANS) functioning affect pH delivery systems in the muscles? In two ways, it turns out; because the ANS appears to regulate ion channel (i.e. H+) transporter activity in the muscles, impaired functioning could impair the muscles’ ability to get rid of protons. As was noted earlier, the ANS also regulates blood vessel functioning, suggesting that altered ANS activity could result in constricted blood vessels (and/or low blood volume) – thus impairing blood flows to the muscles and therefore H+ removal from them.
Could the reduced ability to cleanse the muscles of acid forming protons cause ME/CFS? Studies have shown that effective proton transport is associated with the resolution of fatigue. Indeed the study findings may fit with Light’s receptor work if increased intramuscular pH levels over time produce a feedback signal to the brain resulting in increased sensations of fatigue/pain.
Here, too, though, they could find no differences in mitochondrial oxidative functioning.
Take Away Points From the 2010 Exercise Studies
Energy Production Problems in ME/CFS Are Validated – perhaps the most important outcome of the 2010 research was the validation by three studies of the Pacific Fatigue Lab’s core findings – that energy production is inhibited (and perhaps uniquely so) in ME/CFS .
Symptom Upregulation is Validated – three studies validated the very unusual finding of increased pain levels after exercise which lead to the authors suggesting that ‘central’, i.e. central nervous system, pain processing centers were acting abnormally.
Immune Factors May Play a Role – Two studies did not indicate immune factors play a role and one finding, in particular, suggesting that abnormal complement C4a activation was not taking place: a blow given prior findings. The Light study, however, with its focus on subsetting patients into high PER and low PER groups, however, found plenty of evidence of cytokine upregulation and may push future studies to take symptom subsets into account when they analyze their data.
New Possibilities Showed Up – two studies broke new ground with their findings that acid removal from the muscles was inhibited in ME/CFS and that nitrate levels were greatly increased during exercise. Both studies also suggested that oxygen delivery to the tissues – due to either low blood flows or low blood oxygen levels (or both) could be responsible. The low blood flows could be caused by a number of factors including, ironically, low endothelial NO levels in blood vessel walls that prevent them from dilating enough to get oxygen into the tissues, low blood volume, sympathetic nervous system dysfunction.
Mitochondrial Dysfunction Theory Takes Some Hits – A New Focus Emerges? – Two studies suggested that mitochondrial dysfunction, long a hot topic in ME/CFS, was probably not causing the exercise problems. The mitochondrial issues have not been settled but it will be interesting to see if researchers begin to focus more on examining blood flows to the tissues and why that blood flow may be impaired.
Small Studies – Most of these studies are quite promising, but one unfortunate similarity in them is their small size; often under 20 patients – indicating that these researchers are probably strapped for funds. These studies are small enough to make them quite preliminary; bigger studies will be needed to validate these findings.