Reprinted with the kind permission of Cort Johnson and Health Rising.
By Cort Johnson
It was a typically warm July southern Florida day as we pulled out of our hotel to find one exit blocked by construction. Google Maps sent us in another direction, and when that didn’t work out, we made our own map and, once again, hurried with time running out to our destination – the huge Veterans Administration (VA) building in Miami.
The traffic, everywhere we went, was consistently heavy. Plus, Google seemed to have entered into a Bermuda triangle of its own, frequently telling us to go down one street and then do a U-turn. We made it to the building with minutes to spare. As we rushed through the warren that is the Miami VA – corridors everywhere – our confused faces must have given us away as we were helpfully directed several times to our destination.
I was there for a men’s ME/CFS exercise study. I was going to get on the bike, and exercise as hard as I could while getting blood drawn several times during and then after the exercise test. Dr. Klimas’s team was then going to analyze 9 million data points (covering gene expression, cytokines, flow cytometry, cell function, neuropeptides) captured from the test. This was all happening because of Dr. Klimas’s foresight in having chronic fatigue syndrome (ME/CFS) included as a control group for a Gulf War Illness study.
The idea of getting an exercise test and immune and other data was enticing and had prompted the idea of an East Coast trip, which ended up consisting of stops in Miami (Klimas exercise study), Baltimore (Vicky Whittemore and Avindra Nath interviews), Nashville (Dysautonomia Conference), Tuscaloosa (Dr. Skip Pridgen) and Birmingham (Dr. Jarred Younger).
So here we were in a small office in the big VA. Cognitive tests and the exercise test took up the first day and more cognitive tests were conducted on the second day. On the second day, I fasted in the morning, ate a prescribed breakfast at the facility, and then an hour or so later, did the exercise test.
Graham Salmun, the young exercise physiologist who provided the test, was very welcoming and more than happy to provide answers then and later in email. (It turned out that Graham, a triathlete, had had his own, thankfully temporary ME/CFS-like experience when he’d suffered from overtraining syndrome and was unable to exercise for a month.) It was testament to the strength of Dr. Klimas’s research program that by the time he got to me he’d done over 140 exercise tests in ME/CFS and/or GWS patients.
The test was explained, they got me on the bike, inserted shunts into both arms, and I started pedaling. I’ve done several exercise tests, but this one, for whatever reason, was the worst. It was a miserable slog all the way. I gritted my teeth and pushed as hard as I could until they stopped me.
Feeling somewhat loopy and sleepy after getting a saline IV, my partner and I went to the hotel, took a nap, and afterwards, for the most part, I was fine (!). That was the first time I’d gotten an IV after an exercise study and it worked.
The next day brought more cognitive tests and the scores from the first day’s tests, most of which were at or near normal range, but a few of which were not just low but shockingly low.
Graham, who has since moved on to a post-graduate program at another institution, was kind enough to go over some of the bike test results immediately.
Exercise Test Results
It turned out that I’d lasted for a long time on the bike – over 10 minutes, and could have lasted longer. That actually didn’t surprise me. About fifteen years earlier, ME/CFS and all, I’d actually outlasted my healthy twin, Cass, on the bike in an exercise study.
I regularly walk – not long distances – but I do it regularly enough that I assume I’m not deconditioned. The test did indicate, though, that I hit my anaerobic threshold early – in about half the time a healthy person would have.
Then Staci Stevens of Workwell – an exercise physiologist who has specialized in ME/CFS for years – took a closer look. Even after years of reporting on Workwell’s exercise results, I was astonished how much data she could get out of this report, which didn’t include several parameters (blood pressure, workload) that Workwell includes in its reports. (Those measures were taken but weren’t included in the data I was given.)
In general, my results suggested, as expected, that I have a mild to moderate case of ME/CFS. Even at that, it suggested I was probably not producing enough energy to comfortably carry on the daily tasks associated with living.
Oxygen Uptake at VO2 Max – My oxygen uptake at max VO2 peaked at less than 75% of predicted. Since a sedentary healthy person would be expected to hit 85% of predicted, that result suggested to Staci that I had a metabolic issue that went beyond deconditioning.
Oxygen Consumption at Anaerobic Threshold – My oxygen consumption at anaerobic threshold – 12.5 ml/kg – indicated a mild to moderate impairment. Since > 14 ml/kg provides the reserve needed to do daily tasks, I probably wasn’t generating enough energy to comfortably do the normal tasks associated with daily living.
Heart Rate at Anaerobic Threshold – My resting heart rate was high (89 beats per minute (bpm)) and could have resulted from pre-test jitters. My heart rate at anaerobic threshold – the point at which most of my energy is being produced anaerobically – was a mere 98 bpm. That suggested, if the resting heart rate was correct, that I had a quite small activity window before my system spiraled into anaerobic energy production causing me fatigue and pain.
Staci’s heart rate-based exercise program would have me keeping my heart rate below 98 bpm.
Peak Heart Rate – My peak heart rate was 148 beats per minute, in the low normal range, but a good distance from 177 beats per minute (my expected maximum). That suggested that some chronotropic incompetence – an inability to get the heart rate up to speed – might be present.
Ventilation and Breathing Frequency – my ability to move air in and out of my lungs – was very good – even better at 114% of predicted. That’s fairly unusual in someone with ME/CFS. But my breathing frequency (breaths per minute) at the end of the test was surprisingly low – just 30 breaths per minute compared to the expected 60. I was breathing more slowly, but possibly more deeply, as well. By the end of the test my body had been relying mostly on anaerobically produced energy for about 6 minutes. My lactic acid, which had built up enormously, should have been triggering my lungs to breathe more and more rapidly to buffer it. Staci suggested that the message to breathe more rapidly may not have gotten through.
Stroke Volume – A graph showing heart rate and oxygen consumption suggested I may have lower than normal stroke volume. Stroke volume refers to the amount of blood the heart pumps out during each stroke. That suggested possible autonomic nervous system or cardiovascular issues.
Effort – My respiratory exchange ratio (RER) indicated that I’d given a maximum effort.
Blood pressure or watts/workload measures were taken but not provided in the data I was given. The blood pressure results would have been interesting as blood pressure should increase during exercise, but in some ME/CFS patients, Staci said, it actually drops – a sign of autonomic instability.
Heart Rate Monitoring – Staci said that a heart rate 10 beats per minute higher or lower than usual upon awakening indicates that you’ve done too much. An early morning reduced heart rate, Staci said, is an ME/CFS thing – she doesn’t see it much otherwise, and it is also probably a sign of autonomic instability.
Biological Validation – The Univ. of Miami group I visited does not do biological validation to calibrate their machine – something Workwell recommends. Biological validation involves using a healthy person with known values to help calibrate the machine. My guess is that most exercise physiologists do not use biological validation, but in Staci’s experience, when biological validation is not used, the results tend to read higher (i.e. healthier) than actual. Therefore, my actual results might be lower.
A two-day exercise test done at Workwell or with Betsy Keller would have provided much more information on the resiliency of my aerobic energy production capabilities. I plan to do one at some point. Check out more on their two-day exercise tests below.
Exercise and Chronic Fatigue Syndrome (ME/CFS)
Salmun emphasized that he was providing his opinions based on his research and clinical experiences and that they may or may not comport with the experience of the others working with Dr. Klimas.
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Salmun and Jeff Cournoyer, the lead physiologist in the study, recently presented an abstract on ME/CFS at the ACSM (American College of Sports Medicine) 2018 Annual Meeting and at the VA Research Fair. (Graham expects more studies from the exercise physiology arm of the study to come out.)
Salmun believes that some people who do fine on the test probably have autonomic nervous system problems. Otherwise, lots of different problems are showing up in the exercise tests, but one general energy production issue in both ME/CFS and GWS stood out: reduced metabolism of the key substrate in aerobic energy production – fat. In fact, Graham had just presented on this subject in Minneapolis at the 2018 ACSM conference.
That 20-person study (14 ME/CFS patients; 6 healthy controls) measured fat oxidation rates during a maximal exercise test in ME/CFS. The results were astonishing with maximal fat oxidation rates almost 50% lower in the people with ME/CFS (healthy controls – 617 g/day; ME/CFS patients – 339.5 g/day). While small, the study suggested that people with ME/CFS were indeed having trouble burning fats for energy while exercising – and provided another indication that people with ME/CFS are using anaerobically produced energy far more than healthy people.
To Graham Salmun, the problem likely seemed mitochondrial in nature. It’s in the mitochondria, after all, where fat/fatty acid oxidation is used to create ATP – our main source of energy.
Fatty acid oxidation
Salmun believes the energy deficits he’s seeing in ME/CFS probably result from two things:
- fatty acids aren’t being transported into the mitochondria properly; and
- they’re simply not available in the mitochondria to be utilized.
He referred to Booth’s study ‘Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)‘ which found that the more mitochondrial dysfunction there was, the more severe a person’s ME/CFS symptoms were. That quite large (n=191) 2012 study, which Sarah Myhill co-authored, proposed that a major immediate cause of the mitochondrial dysfunction was a lack of “essential substrates” (as Salmun found).
Salmun noted that our bodies tightly control the oxidation of fuels in order to use the most efficient processes to produce energy. Breaking down muscles into amino acids, which are then converted into glucose using a process called ‘gluconeogenesis’, is terribly inefficient and is used only when absolutely necessary, such as during prolonged starvation states. Gluconeogenesis has been described as “an extremely expensive investment with a negative return”.
The concept of starvation has come up before in ME/CFS. In starvation and anorexia, amino acids and fats are used instead of glucose to preferentially feed the TCA or Krebs cycle and produce energy.
Chris Armstrong reported that many of the metabolomic anomalies (reduced amino acids and lipid and increased glucose) he found in ME/CFS are also found in starvation and sepsis. In these states proteins and lipids are used to maintain low energy levels while glucose is used for other matters – such as immune cell proliferation in sepsis.
Armstrong speculated that an infection or autoimmune process may have triggered a sepsis-like condition that resulted in a state of chronic cellular starvation.
Poorly functioning mitochondria do more than slow a cell and its functions down, though. If the mitochondria stay dysfunctional long enough, instead of entering a process of “autophagy” and safely recycling their contents, cells can become senescent, start deteriorating and begin secreting pro-inflammatory cytokines.
Salmun suspects that the broken mitochondria in ME/CFS patients’ cells, then, may be contributing both to the low energy in the disease and to systemic inflammation.
That autophagy issue gave Graham Salmun a clue on some possibly helpful dietary tips for people with ME/CFS. Studies on intermittent fasting/time-restricted feeding (IF/TRF) suggest that it can help cells with mitochondrial damage enter into autophagy and kill themselves off safely. Removing the cells with damaged mitochondria could provide a novel way of reducing inflammation and improve one’s ability to utilize fats for fuel and increase ATP production. Salmun thinks this dietary measure might provide a lot of benefit, in particular, to people with ME/CFS with high levels of mitochondrial dysfunction.
Time-restricted feeding or intermittent fasting involves restricting one’s food intake to a certain period of time – say from 12pm – 8pm each day. Outside of the 12pm – 8pm period, one should only drink water and not consume any calories, liquid or solid.
Check out Dr. Guido Kroemer, an expert on autophagy & intermittent fasting.
Salmun’s prescription for “exercise” in ME/CFS was typical of exercise physiologists who know this disease: do short-term exercises (1 min or so) followed by a rest period of 1-2 minutes.
The results of the exercise test were personally illuminating (heart rate at anaerobic threshold = 98 bpm! Really???) but more exciting was the news that the Miami team appears to be finding problems with fatty acid oxidation – a core part of mitochondrial energy production. My attempts at intermittent fasting have not worked out but it’s clearly helpful for some people with ME/CFS and I will try again to get some more autophagy going and turn down the inflammation a bit.
Lastly, Staci Stevens’s interpretation of the exercise test results simply reinforced how much information these tests can provide. Workwell and allied exercise physiologists recently published a paper that reports on the unique responses people with ME/CFS have to two-day CPET tests and tells exercise physiologists how to do them correctly. A blog on that is coming up shortly.
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Health Rising’s East coast trip provided a wealth of information inspiring the article you just read and the ones below. Next up on the agenda is a new treatment for fibromyalgia, an Avindra Nath interview, and – on the return home – the folks at the Bateman-Horne Center.
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About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on myalgic encephalomyelitis, chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.