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A large CDC exercise study highlights breathing abnormalities in ME/CFS – but points a finger at the muscles.

Part one of a series on breathing and oxygenation in chronic fatigue syndrome (ME/CFS) and long COVID focuses on a large study that prompted a reassessment of what’s happening during exercise in ME/CFS.

Breathing problems – particularly shortness of breath or experiencing “air hunger” – have shown up in chronic fatigue syndrome (ME/CFS) for a long time, but only recently has breathing become a research focus. That didn’t happen because of patient complaints; it happened when exercise studies suggest that something with the breathing had gone awry during exercise.

Diaphragm

A small muscle at the bottom of the lungs is responsible for having us breathe when we’re not exercising.

In a way, that’s not a surprise at all. Breathing, after all, is inseparable from energy production. Breathing is what the body does to deliver fuel (oxygen) to the mitochondria in our cells. It is also the way our body removes the by-products of energy production (carbon dioxide) from our cells. Our breathing fluctuates depending on our energy needs. We breathe more deeply and rapidly during exercise to deliver more oxygen to our working muscles and more importantly, to remove the CO2 that’s starting to build up. Breathing is fundamental to being able to produce energy. It’s also quite a complex process.

The Signaling Process – Breathing is largely an automatic process controlled by a signaling process between chemoreceptors in the aorta in the heart and carotid arteries that supply oxygen to the head that are constantly sending information about oxygen and carbon dioxide levels to the respiratory centers in the brainstem. Increased levels of CO2 – a toxin at high levels – prompt the brainstem to increase breathing depth and/or speed in order to reduce them. On the other hand, decreased levels of CO2 prompt the brainstem to send signals that reduce breathing in order to allow them to build up to normal levels again.

The Muscles – Normal breathing is accomplished via the diaphragm – a thin kind of dome-shaped muscle – that sits between the lungs and abdomen. Its goal is simply to change the lung volume and create a pressure gradient between the inside of the lungs and the outside of them such that air rushes in to fill the void.

To cause an inhale, the diaphragm pulls downward – causing the lungs to expand – producing a drop in air pressure and the buildup of a pressure gradient between the lungs and the outside of the body. The inrushing air produces an inhale. It’s all driven by muscular activity. The phrenic nerve, which runs from the neck to the diaphragm, controls the movement of the diaphragm. When we’re active, though, the abdominal muscles help us breathe more quickly and deeply.

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It’s clear that in order for the breathing process to work correctly, a number of things have to happen: the chemoreceptors have to correctly sense the gases present, and correctly send the right signals to the brainstem; the brainstem has to correctly process them, then send the correct signal to the muscles that move the lungs; which then have to correctly move them.

While exercise and breathing are intimately connected, only recently have exercise tests in ME/CFS begun to focus more on ventilation – the process of moving air through the lungs – in ME/CFS. This is partially because standard measures of ventilation haven’t been very revealing. More findings have suggested that energy production is limited, and that people with ME/CFS blow through their aerobic energy production capacity quickly and hit their anaerobic threshold. When that happens, energy production drops and symptoms increase dramatically.

Recently, though, both tilt-table and exercise stress tests suggest that a large subset of people with ME/CFS or long COVID often exhibit hypocapnia – abnormally low levels of CO2 – caused by hyperventilation (abnormally deep and/or rapid breathing). In fact, one study found that hypocapnia was far more common in ME/CFS than other forms of orthostatic intolerance such as postural orthostatic tachycardia syndrome (POTS).

Move Over POTS – Hypocapnia May be a Bigger Deal in ME/CFS

Since low CO2 levels can produce many of the symptoms found in ME/CFS / long COVID it’s possible that an altered breathing pattern could play a major role in these diseases. With the hypocapnia findings, more focus has been placed on understanding how people with ME/CFS and long COVID breathe – particularly during stressful situations such as exercise, standing, or even in some cases sitting up.

Exercise Study Prompts Reassessment

A recent large study, “Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study,” took the breathing issue to an entirely new level.

This wasn’t just any study. It was a 403-person (!) exercise study from the CDC’s big multi-site study. Featuring patients from a bevy of ME/CFS experts, it’s the first major study to come out of the multi-site study which began long enough ago for most of us to forget it had ever happened.

Conducted by Dane Cook Ph.D.- an exercise physiologist who’s been studying exercise, pain, and brain functioning in ME/CFS, Gulf War Syndrome, and Alzheimer’s for over 20 years – it was one of the biggest cardiopulmonary exercise (CPET) studies yet done in ME/CFS, and if its authors are correct, the most rigorous.

Fitness chronic fatigue syndrome

When Cook controlled for fitness, some of the abnormalities of energy production disappeared.

Cook and friends have called into question whether past exercise studies have adequately taken into account the low fitness levels that naturally accrue to post-exertional disease.

To attempt to remedy that, the study compared people with ME/CFS to “fitness-matched healthy controls”. These were controls who exhibited near-identical peak oxygen consumption during the exercise test; i.e. at their peak, they produced the same amount of energy as did their counterparts with ME/CFS.  (They tended to be in the low-normal range). They also discarded about 10% of the patients who didn’t meet their criteria for producing a maximal effort (certain heart rate level). (Having 90% of the ME/CFS patients meet the criteria for maximal effort was a good number.)

Once they matched for fitness, they found that ME/CFS patients did not hit their anaerobic threshold at lower levels of peak oxygen consumption, heart rates, lactate or work levels (watts). They suggested these are all the result of low fitness and do not reflect inherent problems in ME/CFS. Nor did they find increased rates of lactate production in ME/CFS.

(I’m not sure if I’m understanding this right but could there be a chicken and egg problem here? Did the patients who did not meet their age-adjusted expected heart rate not meet it because they had chronotropic incompetence? Some studies have concluded that problems with energy production actually preclude people with ME/CFS from reaching their expected maximal heart rate. Could the ME/CFS patients’ peak VO2 levels reflect low fitness because of their problems producing energy?

Is that kind of low fitness different from that found in healthy controls? If healthy controls have low fitness because they don’t exercise much and ME/CFS patients have low fitness because they can’t exercise – doesn’t that matter? Could Cook’s decision to treat low fitness healthy controls and low fitness ME/CFS patients the same – lead to the reintroduction of graded exercise therapy (GET) in an attempt to increase the fitness levels of ME/CFS patients? The paper does suggest CPET-guided exercise programs might be helpful – which is good – but one wonders if it’s inadvertently opened some wiggle room for other exercise prescriptions ).

At this point, the group seemed to be well on their way to erasing any idea that exercise is impacting energy functioning ME/CFS. As we’ll see, that wasn’t true at all. In the end, in fact, the authors actually arrived at a similar place as other researchers – they just came to it from a different direction.

A Gas Exchange Disease?

The big problem this big study found concerned gas exchange – the ability to perfuse oxygen into the muscles and remove carbon dioxide from the blood. The ME/CFS patients did reach their anaerobic threshold at lower levels of ventilation, at lower levels of ventilatory efficiency, and with fewer breaths – and here was the kicker – while moving more air overall. (These indices were also reduced at their peaks).

Remembering that breathing = energy, the people with ME/CFS exhausted their aerobic energy capacity with fewer breaths than did the healthy controls. The authors concluded they had “inefficient exercise ventilation”. The findings were:

  • VE/VO2 – increased
  • VE/CO2 (ventilatory efficiency) – increased
  • VT (tidal volume) – increased
  • fR (breathing frequency) – reduced.

VE/VO2 increased –  VE/VO2 is the amount of ventilation or breathing done relative to the amount of oxygen consumed; i.e. the amount of energy produced. (Oxygen = energy). To put it in simpler terms, it revealed that people with ME/CFS were doing more breathing to produce energy than the fitness-matched healthy controls. Plus their breathing didn’t go as far: they entered their anaerobic threshold more quickly.

 

Biology of ventilation

“The Biology of Ventilation” from Eleanor Lutz, CC0, via Wikimedia Commons

Cook explained that this breathing pattern may be an attempt to improve “alveolar ventilation”; i.e. to get the air sacs or alveoli in the lungs as filled up as possible with oxygen – in order to squeeze as much oxygen as possible into the muscles.

Cook also referred to the “Robin Hood effect” where low CO2 levels (hypocapnia) cause a paradoxical decrease in blood flows when they are most needed. This could result in vasoconstriction or narrowing of the blood vessels in the muscles that move the lungs. Noting that the respiratory muscles are always working, Staci Stevens, an exercise physiologist at Workwell Foundation, suggested some time ago that fatigued respiratory muscles could be causing problems.

High VE/CO2 (ventilatory efficiency) – Ventilatory Inefficiency Elevated – Ventilatory efficiency refers to the amount of ventilation present relative to the amount of CO2 present. The high level of ventilation relative to the amount of CO2 present suggested that the lungs of people with ME/CFS were working harder than usual to get rid of CO2.

This is often due to lung damage that results in increased levels of “dead air space”. The dead air space idea, though, appears to be a dead-end in ME/CFS and long COVID. The lungs appear to be structurally fine – they’re just working strangely. The problem more appears – as the authors noted in their paper – to be a reduction “in perfusion to active skeletal muscle”.

Whatever the situation, the authors noted that the ventilatory inefficiency found in ME/CFS has also been associated with poor exercise capacity and exercise intolerance in other diseases.

A “Unique Breathing Strategy”

Using a more fine-tuned approach than has been done before, the authors uncovered “a unique breathing strategy” in the ME/CFS group. Instead of breathing more deeply and rapidly, the ME/CFS group was breathing more deeply and slowly. As noted above the authors suggested that people with ME/CFS may be breathing this way to increase the oxygen flows to their muscles. In other words, the body is trying to compensate for a problem with energy production at the muscle level.

Interestingly, they found the same unusual – even unique – breathing pattern in people with Gulf War Illness. The fact that this same strange breathing pattern has shown up in these two symptomatically similar, but really quite different, illnesses suggests that at their heart, these two diseases share some core biological features.

Recently, a long COVID study that assessed breathing patterns during exercise found that almost 90% of long COVID patients demonstrated dysfunctional breathing patterns.

Uneasy Breaths: Strange Breathing Patterns in Long COVID May Contribute to Exercise Intolerance

Cook has also done a lot of work on pain and also suggested that this strange breathing could also be the result of an (unconscious) but learned approach to reduce symptoms.

Dane Cook’s Presentation at the ME/CFS Stakeholders CDC Call

Or a Muscle Metabolism Disease?

Their main thrust, though, involved poor oxygen and CO2 extraction. While the authors acknowledged that problems with ventilation and heart rate exist in ME/CFS, and that much remains to be learned, they believe that they’re probably secondary to the real problem – an inability to produce sufficient amounts of energy at the muscle level.

They referred to Vermeulen’s 2014 Dutch exercise study which concluded that the exercise intolerance in ME/CFS was caused by low muscle oxygen uptake (read energy production) by the muscle cells. During the CDC talk, Cook also noted that their results are consistent with David Systrom’s group, which suggests that poor delivery of blood to muscles and poor utilization of oxygen by the muscles is present.

Poor Oxygen Extraction is Contributing to Exercise Intolerance in Chronic Fatigue Syndrome (ME/CFS)

That suggests that the ventilation problem is actually a muscle metabolism problem; i.e. the muscles are getting pushed into anaerobic metabolism – which the body is attempting to compensate for with the strange breathing pattern. That breathing may, however, be producing low CO2 levels (hypocapnia) which may cause more symptoms. Cook did say that breathing exercises might be able to help with that. (A blog on that is coming up.)

The GIST

  • It’s been underway so long that many people have probably forgotten about the CDC’s big experiment that about ten years ago began to assess hundreds of people with ME/CFS who were seeing ME/CFS experts. 
  • The first paper to come out of the big study was a big one indeed: hundreds of people engaged in the biggest exercise study ever done. The maximal exercise study came with a twist: it used peak energy production as a measure of fitness to match ME/CFS patients with healthy controls. 
  • The idea was to make sure that ME/CFS patients’ level of fitness – due to their disease or inactivity – was not skewing their findings downwards. The authors concluded that several measures of energy production (oxygen consumption, reduced heart rates) that have prominently figured in the ME/CFS literature, reflected the low fitness levels found in ME/CFS and were not inherently a part of the disease itself. (See the blog for some questions about that.)
  • On the other hand, problems with breathing were found even in the fitness-matched groups. The core finding concerned problems with “gas exchange”; i.e. the ability to get oxygen into the tissues and remove carbon dioxide. This showed up in the ME/CFS patients having to breathe more to produce energy and remove carbon dioxide. 
  • A deeper dive into the breathing patterns found that the people with ME/CFS were breathing more deeply and more slowly during exercise than the healthy controls. Dane Cook, the leader of the group, suggested in a CDC talk last year, that the ME/CFS patients were trying to load the air sacs in their lungs with more oxygen. 
  • It’s also possible that hypocapnia – low levels of CO2 caused by that breathing pattern – may be vasoconstricting the blood vessels leading to the muscles moving the lungs – causing muscle fatigue and these strange breathing patterns. Another possibility concerns an attempt to avoid pain that ends up shutting down motor signals from the brain that tells the body to move and causing fatigue. 
  • The study results suggesting poor oxygen extraction by the muscles in ME/CFS fit with several past findings including David Systrom’s invasive exercise studies. While a variety of issues could be contributing to this including deformed red blood cells  Cook appeared to be most interested in the possibility that mitochondrial issues were to blame. 

His best bet at this point, though, appears to be on the mitochondria. At the CDC talk, Cook said they would have looked at mitochondrial functioning in every way possible if they had been able to. They also left open the possibility that deformed red blood cells, that are having trouble wending their way through the small blood vessels and delivering oxygen to the muscles, might be causing problems.

Increased Perception of Effort

The biggest difference between the ME/CFS patients and the healthy controls, though, was how much more difficult the ME/CFS patients perceived the exercise to be. I wonder if anyone would disagree with the authors’ assertion:

“Based on the preponderance of data, it can be concluded that people with ME/CFS perceive exercise as requiring more effort than otherwise healthy people.”

That could be because the pain they’re experiencing basically causes the brain to shut down signals to the muscles – which makes it harder to get them to move. The authors went back to a small 1999 study which suggested that the increased perception of effort in ME/CFS was associated with a “diminution in central motor drive“; i.e. the motor centers of the brain are not giving the muscles the signals they need to move. When that happens, you have to focus and push harder to get those signals telling the muscles to move through – thus experiencing an “increased perception” of effort.

A similar scenario may be occurring with regard to mental effort. The slow information processing and poor sensory filtering processes appear to make cognitive tasks more effortful in people with ME/CFS/FM. In the same general way that ME/CFS patients’ lungs may be working harder to provide oxygen to the muscles, the brains of people with ME/CFS have to exert more effort in order to compensate for the slowed information processing and the diversion of mental resources that comes part and parcel with these diseases.

Deconditioning Hypothesis Slammed

Finally, Cook emphasized how damaging the idea that ME/CFS is a disease of low aerobic fitness (i.e. a disease of deconditioning) has been. Speaking as an exercise physiologist, Cook stated there was no scientific reason to believe that. He called it a “false narrative propagated by non-exercise scientists” which has “produced a lot of noise” and has held up the field. Ironically, Cook argued that poor aerobic fitness – not a pathophysiological problem – was responsible for the false findings of low VO2, etc. in ME/CFS. but then asserted that efforts to blame low aerobic fitness for ME/CFS were wrong.

The authors noted the limitations of CPET studies. For one, they can suggest that problems with oxygen delivery exist, but they can’t show that they do. For that, we need … invasive exercise studies – which we certainly have 🙂 – and more sophisticated tests of ventilatory and mitochondrial functioning. They also noted that the problem is probably worse than the studies show, as only the healthier people with ME/CFS tend to volunteer for exercise studies.

Conclusion

One of the strangest studies yet, this study first appeared to overturn about a decade of thought on the exercise situation in ME/CFS. Using hundreds of patients from ME/CFS experts, and healthy controls, the fitness matching of ME/CFS patients to healthy controls caused energy production problems like an inability to reach peak VO2 and to achieve normal heart rates during exercise to disappear. In place of those, though, the study found that people with ME/CFS manifested a strange breathing pattern (deep and slow) which left the lungs working overtime to get oxygen into the muscles and remove carbon dioxide from their blood.

Whether or not the fitness matching was necessary the authors were left with a similar conclusion as past studies: poor energy production at the levels of the muscles was probably driving the breathing and exercise problems in ME/CFS. The authors suggested that during exercise, people with ME/CFS were attempting to (subconsciously) compensate for the problems with gas exchange at the level of the muscles by breathing more deeply and slowly – thus driving more oxygen into their lungs. By doing that, though, at least some of them may be reducing their CO2 levels – causing symptoms similar to those found in ME/CFS. It’s also possible that fatigued respiratory muscles, poor signaling from the oxygen and CO2 receptors, or brainstem problems were playing a role.

Ultimately, though, Cook appeared to put his money on mitochondria problems – leaving him in a similar place to the other exercise physiologists who have studied ME/CFS.

Check out a clinical trial that’s trying to change how people with ME/CS and long COVID breathe in order to increase their CO2 levels.

Breathing Better in ME/CFS and Long COVID? The Inspiratory Muscle Training Trial

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