Central Findings

  • Only maximal  (exercise to exhaustion) exercise tests reveal the problems with energy production  in Chronic Fatigue Syndrome
  • Weakened muscles that move the lungs may, because of oxidative stress/mitochondrial problems, be stopping people with ME/CFS from getting oxygen to their muscles
  • A large study suggested that reduced oxygen extraction at the muscles could be due caused by mitochondrial problems
  • A small submaximal exercise study suggested that almost 20% of ME/CFS patients have mitochondrial problems
  • A study examining exercise intolerant individuals who may or may not have ME/CFS suggested mitochondrial problems were likely
  • A Japanese metabolomics study suggested problems with ATP production were rampant in ME/CFS

I believe that the buck stops in Chronic Fatigue Syndrome at ‘exercise intolerance’ (physical or mental). Whoever can figure out what’s causing that will bag ME/CFS.


Could it be the mitochondria? Although the evidence is preliminary several exercise studies are pointing at them.

That makes exercise studies very interesting. In past conference we mostly saw researchers using two-day exercise tests trying to prove that exercise further depletes an already-depleted energy production system. In this conference they mostly stopped doing that; now they’re trying to get more at the cause. In a rather startling convergence no less than five studies pointed at the mitochondria.

That made the ‘Provocation’ session, as the IACFS/ME called it, very provocative indeed – and it makes the Chronic Fatigue Initiative’s focus on the mitochondria look like a very smart call right now.

First, though, we’ll look at another study that validates the two-day exercise test results. More validation is needed, but probably not from these groups; we really need it to come from an outside research group.

Validating the 2-Day Test – Saying Good-bye to Submaximal Tests

Dr. Keller did a good job of closing the door on submaximal exercise tests in Chronic Fatigue Syndrome. These are tests that measure oxygen uptake at less than maximum energy expenditure. Theoretically they should work in Chronic Fatigue Syndrome; that is, you should be able to calculate oxygen uptake, heart rate, etc. at exhaustion using submaximal exercise test results and draw up a suitable exercise plan, but people with ME/CFS don’t fit the curve. (Since when did they fit the curve?)

inaccurate sign

Submaximal test results have been used to produce damaging exercise prescriptions but more sophisticated tests indicate they are inaccurate and misleading

In fact, Keller stated that none of the four assumptions underlying the accuracy of submaximal tests may hold true in ME/CFS.

The problem is that their energy production systems poop out as they get more stressed and the submaximal test misses that. According to those tests they’re pretty normal. Keller stressed that, because submaximal tests make ME/CFS patients appear more functional than they are, they can (and have) been used as the basis for a prescription to exercise.

The only way to get at the functional impairment during exercise is to do a maximal exercise test (exercising to exhaustion… it doesn’t take long), and if the problems don’t show up the first day, then they probably will the second day.

Keller looked at about 40 people with ME/CFS. Her results were a little confusing. She was unable to find diminished ‘functional capacity’ in ME/CFS after one CPET (maximal exercise test), yet she said it occurred in 55% of ME/CFS patients. Two CPETs (on successive days) on the other hand uncovered ‘functional impairment’ (reduced VO2 max at exhaustion or at anaerobic threshold on the second test) in 98% of her subjects.

Now, that is a significant result.

Van Ness’s Ventilation Study – Mitochondrial Problems? – Round I

Workwell (Pacific Fatigue Lab) was the first research group to identify the exercise problems in ME/CFS, and in this study Van Ness announced they’ve identified a possible cause: poor ventilation. Ventilation refers to the amount of oxygen you breathe in and CO2 you breathe out.

As you exercise you need to breathe in more oxygen (to supply the mitochondria in your muscles) and breathe out more CO2 (to remove the waste buildup in your muscles). If you can’t breathe fully enough, you can get hit twice during exercise; first, muscles can’t produce the energy they need, and second, you’ll get whacked from all the CO2 building up in your system.

Van Ness found reduced ventilation in ME/CFS that was (get this!) proportional to the reduction in VO2 max seen. That suggested he was getting close to an answer.


Reduced ventilation suggested the muscle moving the lungs are pooping out at higher exercise levels

Van Ness made it clear that the lungs were working fine; he believes it’s the muscles that pump the lungs that are punking out. These are among the most active muscles in the body — they never stop unless you stop. He proposed that either high levels of oxidative stress are inhibiting the mitochondria, or the autonomic nervous system drive (which is responsible for telling them to move) is damaged.

Intuitively, at least for me, this makes a lot of sense. For whatever reason — and we’re going to see a reference to this in the Rowe presentation — my upper torso has tended to be rigid and unbending; it feels ‘stuck’ and it feels like its been decades since I’ve taken a really deep breath.

Poor Oxygen Extraction – Vermoulen’s Big Study in Holland – Mitochondrial Problems? – Round II

Vermoulen then blew everyone away with his study. It wasn’t just his findings, but the extent of what he did. Over a period of six years, Vermoulen appears to have given an exercise challenge to every one of the over 200 patients who came into his clinic suffering from significant fatigue.

He also did something no one else has done: he measured the ‘oxygen pulse’, the amount of oxygen that goes through the heart with every heartbeat. Then he compared that to the patient’s cardiac output.

Apparently a pretty standard ratio of oxygen content to cardiac output is found in healthy people as well as people with diseases.

If my notes are right this ratio was off by a huge amount in his ‘CFS’ patients. (My typing had deteriorated to this (“Normal oxyten estreaction – 13.8 – increase of cardica outple relative to incerase of ocsyten uptate” :)) at this point in the conference.

An approximately 50% higher ratio of cardiac output relative to oxygen content indicated that the hearts of ME/CFS were working really hard relative to the oxygen being inhaled and taken up by the muscles.

It wasn’t that the heart was overworking; it was that the increase in blood oxygen levels expected as the people with ME/CFS exercised harder and harder didn’t materialize. Their hearts were pumping like they should to drive the oxygen-laden blood to the muscles, but the oxygen wasn’t being taken up as it should be. The peak oxygen consumption in his patients was 25% lower than normal.

Interestingly, Vermoulen found that his fatigued patients who did not meet the Fukuda criteria had similar exercise results to those who met the criteria.

Van Ness had just pointed to oxidative stress – which would affect the mitochondria – as a possible cause for the low oxygen consumption in his group, and now Vermoulen fingered the mitochondria as well.


Vermoulen suggested mitochondrial problems could be causing the low oxygen uptake in his fatigued patients

He noted that if the mitochondria are recycling ADP, Pi, and H+ properly and too many protons are building up, the cell will use lactate to get rid of the H+ (protons) and thus protects itself from acidosis. But he was finding low lactate levels.

That suggested that either there was a problem with forming lactate (which would lead to metabolic acidosis as protons (H+) built up) or it could reflect an energy production system that had been downregulated (possibly to protect the cells.) It was also possible that damaged mitochondria were producing more protons that than the lactate could sop up.

As Vermoulen went through a couple of case histories he noted that he has a lot of metabolic acidosis cases, but he also portrayed people with different metabolic abnormalities. It appears there’s more than one “road to Rome” leading to producing exercise intolerance.

Canadian Submaximal Test Finds Evidence of Mitochondrial Abnormalities in @20% of ME/CFS – Mitochondrial Problems – Round III

This small Canadian study (from researchers new to ME/CFS) that used a handgrip as an exercise tool found that almost 20% of people with ME/CFS showed evidence of mitochondrial abnormalities. The lead presenter, Dr. David Patrick, has big plans for further studies, including one involving an exercise challenge and a wide ranging gene expression test. He said he thought the prospects for landing the grant are good.

Regardless of whether he succeeds in getting this grant, you can add Patrick and his colleagues at the Complex Chronic Disease Study team in British Columbia to a growing list of researchers interested in exercise and ME/CFS. Dr. Patrick is the Director of the University of British Columbia’s School of Population and Public Health.


Discrepancies in the results do keep popping up. Notice that the 98% of the people with ME/CFS in the Keller study had either reduced V02 max at anaerobic threshold or at VO2 max. This mirrors findings in other studies. Keller said she’d hoped her study would bring some clarity to this situation, but she acknowledged that her mixed results had just added to the confusion. She believes bigger studies are needed.

Then we have the significantly reduced ventilatory response in the Van Ness study, and the normal ventilatory response in the Vermoulen study. These differences may be problems of study size and different types of patients and/or a variety of metabolic problems that exist which show up as exercise intolerance.

The most important thing is that everyone, thus far using mostly small studies, is finding dramatic metabolic abnormalities during exercise. That suggests that the dramatic symptom in ME/CFS – Post-Exertional Malaise (PEM) – is slowly being pathophysiologically documented. Larger studies, Keller thought, would clear up the confusion.

A large rigorous study with well-documented ME/CFS patients from a top-notch researcher outside the ME/CFS field would probably get this oh-so-intriguing aspect of ME/CFS going.

In fact, it’s possible one such study could get under way as a result of this conference, which brings us to the next exercise study. As I ambled along the poster presentations I kept noticing a young woman (Dr. Melamed) who, in contrast to other poster presenters, actually stood by her poster during the breaks.

The Surprise of the Conference – Impaired Oxygen Extraction As a Cause of Unexplained Exertional Intolerance – Mitochondrial Problems Round III

As I took a glance at it I was shocked. It was an exercise study from a researcher I’d never heard of, but it was not a study of ‘ME/CFS patients’ (or so it appeared), but a study of people with unexplained ‘exercise intolerance’.

The reason we don’t know if they were ME/CFS patients is that they simply didn’t check. All we know is that they showed at this doctor’s office complaining of ‘exercise intolerance’.

The Systrom group went straight to the arteries to assessing oxygen exchange in exercise intolerant individuals

The Systrom group went straight to the arteries to assessing oxygen exchange in exercise intolerant individuals

This study took a different tack. Instead of measuring oxygen consumption using the breath, they inserted catheters into their radial and pulmonary arteries and measured it there. (This is called Invasive Cardiopulmonary Exercise Testing (CPET), and the senior author is highly in favor of that. He recently wrote a review paper extolling the benefits of ‘Invasive Cardiopulmonary Testing’.)

This large study looked at 257 consecutive patients over two years. It was a little hard to understand the results, but they concluded, just as Vermoulen did with his ‘CFS’ patients, that

“Abnormal oxygen extraction is common in people with unexplained exercise intolerance”

Another conclusion that “associated hyperventilation may further compromise oxygen extraction” appears to fit in very well with Newton’s recent finding, and finally their statement that

“mitochondrial dysfunction of the carotid body or skeletal muscle may account for the hyperventilatory and hypercirculatory responses”

appears to fit in with Van Ness’s findings suggesting that skeletal muscles are not working properly to move the lungs in ME/CFS. Stating that Dr. Systrom had moved one step forward with his measurement of oxygen in the blood, Van Ness said the ‘kinetics’ of the Boston study fit what they were finding.

I asked Dr. Melamed if Dr. Systrom was interested in studying people with documented chronic fatigue syndrome. She said she thought he was. (How could he not be if he flew her across the country to present this poster?)

Would Dr. Komaroff, our Mass contact, be interested in providing patients to her? Yes, he stated, he would be. The two met, and it turned out that he works in the same hospital as Dr. Systrom. We’ll see what happens.

Who is this lead author of the study? David M. Systrom MD just happens to be a very well published researcher in this field. He publishes on exercise studies frequently. Could he be the one to legitimize the energy production problems in ME/CFS? We shall see, but the fact that this Boston researcher knew enough about the exercise problems in ME/CFS to send a Ph.D. across the country to give a poster presentation on their exercise intolerance findings was remarkable.

We’re not done yet though. Another poster presentation perked up some eyes, particularly Suzanne Vernon’s, as well.

Metabolomics Study Suggests ATP Production is Significantly Lower in ME/CFS: Mitochondrial Problems – Round IV

At the other end of the hallway was another poster, Suzanne Vernon shouted to me as she passed by, saying it was ‘very important’.

In the CFI report we learned that Mady Hornig MD is in the midst of a metabolomics study in ME/CFS, but she’s not going to be first. Across the Pacific, in Japan, researchers have already done one and the results were fascinating.

Metabolomics involves the study of metabolites in the blood. The Japanese researchers found that levels of organic acids related to glycolysis and the tricarboxylic acid (TCA) cycle were significantly lower in people with chronic fatigue syndrome than in controls. That suggested decreased ATP production was present in ME/CFS. The abstract boldly stated that the finding will lead to a biomarker.

A biomarker indicating problems with energy metabolism would fit so nicely that it makes my toes curl just thinking about it.

Are the stars converging? This is complex stuff, but it appears fit in with the idea that reduced muscle activity is stopping ME/CFS patients’ lungs from getting enough oxygen in, and with Vermoulen’s suggestion that mitochondrial problems are preventing normal oxygen uptake by the muscles. It also fits with the mitochondrial problems the Systrom study found in its exercise-intolerant patients.

A Slowly Expanding Field

First there was Workwell (Pacific Fatigue Lab), and then Vermoulen showed up. Now Betsy Keller has done two studies. Patrick Kane of Vancouver is now involved. Dr Enlander and a pulmonologist are engaged in a major exercise study.  Perhaps David Systrom will be as well. Gordon Broderick at NSU is modeling blood flow.

A growing and converging field? Time will tell

A growing and converging field? Time will tell

We can look forward to probably three publications in the next six months or so on exercise intolerance in ME/CFS. Word is getting around. My guess is that, as long as we keep getting positive results, this field is going to grow, more researchers are going to join in, and we’re going to get closer to the answers for the exercise/activity problems that dog us all.

Dr. Hornig believes the gut studies are going to break this disorder wide open leading to a boom in research similar to what’s happened in autism (See Taking the Initiative: the CFI Reports). I think exercise studies could do that.

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