The wind blew like mad all four days of the conference. Maybe those are winds of change…

A sense of excitement and hope I hadn’t seen before pervaded this conference.  More than anything else, this was a conference of possible beginnings. Fields of inquiry such as metabolomics are being opened up that promise much. Time, of course, will be the great arbiter, but right now hope is in the air.

breakthrough-wallDr. John Whiting, who’s been attending these conferences for years said it rather feels like the Berlin Wall falling – things seem to be dropping into place. Let’s hope so. One thing seems sure; the next  year or two are going to be exciting. Dr. Fluge’s statement, “We’re just scratching the surface. Give us a year.” suggested much more is to come.

As new possibilities for understanding the energy problem in ME/CFS emerge, using exercise as a stressor to characterize the effects of energy depletion in ME/CFS are on the rise. Those studies continue to underscore not just how impaired the energy production system is in ME/CFS, but how many ways it can be impaired.

Before that – a note of thanks to an organization we probably too often take for granted. This conference – the 12th conference the IACFS/ME has hosted – brought patients, doctors and researchers from around the world to discuss and collaborate on this disease.

It didn’t have to be. Fibromyalgia, with several times the number of patients, several drug approvals, and much greater public recognition, doesn’t have conferences like these. For whatever reason, that field hasn’t had two figures like Daram Ablashi and Orvalene Prewitt, who, way back in 1990 (when ME/CFS prevalence figures were ridiculously low), declared that this disease deserves a professionally produced scientific conference.

Twenty-seven years later, a still perennially cash-strapped organization run entirely by volunteers keeps finding ways to put them on, giving patients a chance to meet up, doctors to learn and researchers to collaborate. Relationships have been forged that would never otherwise have occurred.

So thanks to the volunteers, now and past, of the IACFS/ME for believing in ME/CFS and devoting your time and energy to ensuring that the community has a place to come together.

(Now let’s do it every year :))

The IACFS/ME 2016 Conference Overviews #1: Energy and Exercise

Metabolomics and Energy

Dr. Fluge : Plenary Session – B-lymphocyte depletion and disease mechanisms in ME/CFS

Dr. Fluge, it turns out, was onto the metabolomic connection in ME/CFS well before most of us were. Struck by the McGregor/Armstrong group’s past work in Australia, he initiated a metabolomics study sometime in the past year. Then he appears to have initiated another study (a gene expression study) based on that study. Plus, he’s been examining the effects of ME/CFS patients’ serum on the energy production in their muscle cells. The man is nothing if not busy.

Fluge stated that symptoms in ME/CFS could easily be caused by defects in the energy production process, and cited both the anaerobic exercise work done by Workwell and Naviaux’s metabolomics work. Like Naviaux, Fluge asserts there’s nothing wrong with the mitochondria; they’re not broken or damaged – they’re simply turned off. That’s probably good news given how complex the mitochondria are.

But how does the success with Rituximab fit into this energy breakdown? Very easily it turns out. It simply requires an immune attack on the mitochondria. Rituximab could, by knocking down B-cell activity, be stopping the production of the antibodies that are whacking the mitochondria in ME/CFS.

blood cells ME/CFS

Something in the blood could be causing ME/CFS

How did Fluge figure out that the mitochondria are not to blame? The same way Ron Davis did. Both exposed cells from healthy controls to the serum from ill ME/CFS patients – and watched those healthy cells poop out. Then when they put ME/CFS cells into healthy people’s serum, they turned into healthy cells. Something in the serum of ME/CFS patients is knocking the heck out of their cells.

Ron Davis will begin bombarding those cells with different factors to see if he can figure out what in their own serum is causing their energy production to poop out.

Neither Fluge nor Davis knows what that is. It could be autoantibodies or it could be something else. Fluge suggested that a subset of aberrant B-cells producing these antibodies could do the trick. Fluge and Mella have apparently been searching for autoantibodies for quite a while, but Davis isn’t surprised that they haven’t found them yet; it’s not that easy to do.

The key may be something called the pyruvate dehydrogenase complex (PDC). Both the Davis Open Medicine Foundation and the Fluge/Mella groups appear to be looking intently at the process of pyruvate metabolism. The end product of glycolysis is pyruvate which then gets altered by the PDC complex so that it can be used in citric acid cycle and aerobic energy production. It’s essentially the bridge between anaerobic energy production and aerobic energy production.

Glycolysis is the part of the energy production process the Australian 2015 metabolomics study suggested was broken in ME/CFS. If pyruvate doesn’t get produced or isn’t broken down properly, aerobic energy production gets stuck in first gear; it’s simply won’t have the resources to get moving. Looking at a diagram, Christopher Snell of Workwell poked a finger at the point where energy production makes its rather momentous shift from anaerobic to aerobic energy production, and said that’s where we always thought the problem occurred.

If I have this right (hopefully), then problems with glycolysis then – not aerobic energy production per se – but the part of the energy production cycle that provides the resources for aerobic energy production may be a key in ME/CFS. It’s possible that the aerobic part of the energy production process is not damaged in ME/CFS; it’s just starved for resources.

Pyruvate dehydrogenase is a main player in carbohydrate metabolism; if carbs aren’t available or something is wrong with PDH, it gets down-regulated and fatty acids are used as an energy source. That’s what the Australians’ data suggest is happening in ME/CFS.

It’s also, as the Aussies pointed out, similar to what happens in starvation. In starvation, the level of PDK enzymes (pyruvate dehydrogenase kinase) increase as the PDH complex stops muscles from using glucose as a fuel and shifts towards using fats and amino acids. Fluge and Mella’s unpublished gene expression study suggests a similar pattern is happening in ME/CFS. It also found that men were more likely to grab amino acids from their muscles to fuel glycolysis but women had more trouble breaking down pyruvate to acetyl-CoA.

Genetic problems with pyruvate dehydrogenase do suggest that something like ME/CFS can occur. They are associated with an abnormal buildup of lactate, low energy and severe lethargy. Pyruvate dehydrogenase has also been pegged as a possible factor in primary biliary cirrhosis – a disease Julia Newton has studied extensively – which shares similar fatigue characteristics with ME/CFS.

Fluge warned that the results are preliminary. We certainly have to be careful. We’ve had several instances of very promising work not pan out recently. Some of Dr. Newton’s very promising work was apparently recently upended, and ten years of Dr. Natelson’s work went down the drain as well. Both published several studies with positive findings until a larger study indicated the work was all for naught.

It’s encouraging that both Fluge and Davis, the Aussies, Hanson and Naviaux are finding similar broad patterns of hypometabolism. Much more is to clearly to come. “We’re just scratching the surface”, Fluge said. “Give us a year…” and we’ll know much more.

POSTER: A Metabolomic and Genetic Analysis of Post Exertional Fatigue in ME/CFS

Neil McGregor was clearly in demand at the conference. His fingers danced in the air as he described the metabolic breakdowns present in ME/CFS.

This serum, fecal matter and urine metabolomics study found that post-exertional fatigue with an adenosine product called hypoxanthine in the serum and uracil in fecal matter. Hypoxanthine should not be showing up in high levels in the serum; its presence there suggested that it was not being transported from the gut to the kidneys where it should be reabsorbed.

An assessment of the genes that transport hypoxanthine found five-fold increases in some of the polymorphisms associated with them.

The McGregor abstract focused on the kidneys but hypoxanthines also affect the muscles. In fact, serum hypoxanthine levels are considered to be a biomarker for the muscle fatigue that occurs as a result of intense exercise. With serum hypoxanthine levels significantly increasing after intense exercise, hypoxanthine is considered to be a good indicator of muscle stress.

ME/CFS patients, of course, are not engaging in intense exercise but, the Australians ME/CFS metabolomics data suggests ME/CFS may be similar to starvation, and similar kinds of muscle breakdown occur in intense exercise and starvation. During intense exercise or starvation – if I have this right – purine compounds are broken down to provide ATP for the muscles. That process leaves behind hypoxanthines in the muscles which are then used to reconstitute purines and keep the flow of ATP going. The hypoxanthines should be used up before they have a chance to reach the blood.

High levels of hypoxanthines in the blood or serum means the muscle cells no longer have a base with which to reconstitute their ATP, and have to start that process over again from scratch. That’s a recipe, of course, for lower energy production. Hypoxanthine levels in the blood have become such a hot topic in athletics that some believe they will replace more traditional training measures such as VO2 max and lactate threshold.

The Mitochondria

POSTER: Marian Dix Lemle – Hydrogen Sulfide Redux (Understandng ME/CFS through the systemic actions of the bioenergetics mediator hydrogen sulfide)

Marian Lemle’s 2007 paper proposed hydrogen sulfide (H2) could be driving ME/CFS patients into a hypometabolic or hibernation-like state. At the Institute for Neuro Immune Medicine’s pre-IACFS/ME conference conference, her work took center stage as Dr. Deth discussed mitochondrial functioning.

In her poster Lemle began the process of updating us on the enormous strides in understanding the role H2S plays in the body. H2S regulates the production in the mitochondria, DNA replication and more. Recent evidence suggests it also plays a role in inflammation, blood vessel functioning or “tone”, neurotransmission and cortisol production.

Children with POTS have been found to have increased levels of H2S and breath tests for H2S may be a biomarker for small intestinal bowel overgrowth (SIBO). H2S may also be involved in mast cell activation, muscle problems and disturbed sleep.


Cooking With Less Fuel – the CDC/ Dane Cook Multi-site Exercise Study

As Fluge and Mella were digging into the causes of the energy problems in ME/CFS, other studies were uncovering more physiological evidence that they exist. Dane Cook’s CDC multi-site exercise study should go a long way to convincing naysayers that vigorous exercise is a no no in chronic fatigue syndrome (ME/CFS). The worries about the one-day test were for naught; the ME/CFS patients showed significant declines in almost every parameter tested.

The Gist

  • An immune system attack on the mitochondria could be causing the energy problems in  ME/CFS
  • Putting healthy cells in ME/CFS patients blood causes their energy production to drop suggests that what’s causing ME/CFS  could be in the blood
  • Problems with the pyruvate dehydrogenase enzyme complex could explain much about the energy problems in ME/CFS
  • Thirty minutes of submaximal exercise caused reductions in ME/CFS patients brain activity and cognitive capability the next day. 
  • High hypoxanthine levels suggest ME/CFS is in some ways similar to starvation
  • lncreased lactate levels during exercise indicate the more toxic, inefficient and far less powerful anaerobic energy production pathway is used more in ME/CFS
  • Reduced heart rates during exercise indicate an inability to appropriately engage the heart during exercise
  • Many different types of exercise dysfunction are found in the ME/CFS community
  • Problems with hydrogen sulfide could explain many of the mitochondrial and other issues in ME/CFS
  • Exercise triggered sympathetic nervous system activity caused about half the ME/CFS patients in a small study to temporarily come down with POTS
  • Dr. Fluge asserted that we will learn much about ME/CFS in the next year


Cook had people with ME/CFS and healthy controls (n=57) do a cognitive test and a brain scan before and after an exercise regimen (30 minutes of submaximal exercise) that some believe is tougher than the exercise to exhaustion test Workwell and Keller use in their studies.

Cook found that the point at which ME/CFS patients meet their anaerobic threshold (percentage of VO2 max) was similar to that found in controls (they didn’t go into anaerobic energy production earlier) but every other test for energy production was impaired.

The key check in this test is something called “peak effort”. Peak effort refers to the ability to reach an expected heart rate and a desired C02/O2 use rate (RER). Exercising hard causes O2 levels to drop as muscles snatch up oxygen to produce energy, and levels of CO2 – a byproduct of exercise – to rise. When the correct peak heart rate and C02/O2 are reached, peak effort has been achieved. Not reaching peak effort puts the other exercise findings in doubt; it suggests that a person is simply not trying hard enough.

More of the ME/CFS participants in the study achieved peak effort (81%) than the healthy controls (78%). Their significantly lower peak oxygen consumption (peak VO2) suggested they weren’t able to produce as much energy. Their reduced ventilatory equivalent or volume (VE) suggested they may have had problems getting oxygen to their tissues. Their lower heart rates indicated they weren’t able to get their heart up to speed. The lower lactate levels indicated problems with energy production. The higher RPE levels indicated they were really exhausted by the effort.

Poor physical fitness alone cannot account for these changes. Sedentary people typically have reduced anaerobic thresholds and increased heart rates and ventilatory exchanges but ME/CFS patients displayed the opposite pattern; they had reduced heart rates, reduced VE and normal anaerobic thresholds. That suggests that their reductions are due to biological limitations.

That was a good result, but that wasn’t the main finding. Cook also found that exercise produced significant cognitive issues the next day in ME/CFS patients. That’s not what is supposed to happen; exercise is supposed to improve cognition, not reduce it. In fact, the healthy controls did better on the cognition tests the day after the exercise and the brain imagining tests showed why. Their brains – apparently freshly invigorated after that exercise – were more active during the cognitive testing the next day, but the ME/CFS patients brains were not; one part of their brains was actually less active. Cook indicated that that meant they had to work harder to produce the same result.

If energy depletion is a big part of this disease, then one would expect it to show up in the biggest user of energy in the body – the brain – and it did.

This study has the potential to be a game

exercise and brain dysfunction in ME/CFS

Thirty minutes of exercise caused both cognitive declines and reduced brain activity in ME/CFS patients the next day. It did the opposite in healthy people.

changer, I believe. It’s large (n=84), it includes multiple sites, and it’s got the CDC’s stamp on it. It shows that a mere 30 minutes of submaximal exercise can whack ME/CFS patients’ ability to think and reduces their brain activity the next day.

Plus, it shows that despite trying as hard as healthy controls, people with ME/CFS can’t produce as much energy and or get their hearts engaged properly. The lower lactate findings are intriguing; some researchers are finding higher lactate levels but the Australians found lower lactate levels – suggesting that even the anaerobic energy production process is blunted in ME/CFS.

 Something New From the Norwegians

The Norwegians’ contributions to ME/CFS – already immense – continue to expand. Katarina Lien of the University of Oslo took exercise testing a step further when she inserted an arterial catheter to assess the levels of lactate – a toxic by-product of anaerobic energy production – every thirty seconds during a two-day exercise test in ME/CFS patients and healthy controls.

Her small study (n=33, all female) added another twist to the exercise testing results in ME/CFS. Lien did find reduced peak oxygen consumption – an indication that ME/CFS patients were not producing as much energy as the healthy controls – on both days, and did find ME/CFS patients’ V02 max drop on the second test, but did not find the drop statistically significant, as other studies have.

Lien did, however, find greatly increased lactate accumulations in the ME/CFS patients during both exercise tests (p<.001). The fact that in the controls lactate appeared at a later time point during the second exercise test suggested that healthy controls actually benefitted from the first exercise session. Lactate’s appearance at an earlier time point on the second exercise test in ME/CFS patients suggested that they were relying more on anaerobic energy production than before.

A similar “left shift in the lactate curve” is found in over-trained athletes.

Not Working Well – Heart Rates Fail to Match Demands

The more researchers dig into energy production and exercise in ME/CFS the more they seem to find. First, problems with V02 max and anaerobic thresholds showed up. Then they found problems with ventilation, and at the conference Mark VanNess of Workwell demonstrated that heart rate is an issue as well.

We know that, particularly at night, resting heart rates can be elevated in ME/CFS, but VanNess asked a very different question: what happens to the heart rate during exercise? It should quickly increase and in the first exercise test it did, but on the second day the peak heart rate the ME/CFS patients were able to achieve was significantly lower than the healthy controls (165 bpm -180 bpm), plus it appeared that the strain of the exercise on the first day caused the ME/CFS patients’ resting heart rate the second day to significantly increase (100-89).

This inability to ramp up one’s heart rate sufficiently in response to exercise – which is called chronotropic incompetence (CI) – is associated in people with cardiovascular disease with reduced quality of life and functioning.

Heart rate chronic fatigue

Another exertion problem; ME/CFS patients’ hearts cannot keep up with the demands of exercise.

Because the testing was done on fairly functional people, VanNess suggested that it probably underestimated the true extent of the CI in ME/CFS. He indicated that it’s not due to reduced blood volume.

The Workwell Foundation Presentation at the NIH on Exercise Testing – We’ve heard a lot about Edward Shorter’s unfortunate presentation – apparently initiated by the Nursing Institute (not Nath’s Special Interest Group (SIG) on ME/CFS) on the “history” of ME/CFS. The SIG’s presentations have been decidedly different: Dr. Komaroff, Dr. Peterson, Lenny Jason and the Workwell group have all presented thus far.

Mark Van Ness said he was very pleased with the reception the Workwell Foundation got. He felt that the interest expressed, the questions asked, and the level of expertise regarding exercise present, suggested that the NIH is indeed interested in figuring this disease out. He was also quite impressed with Brian Wallit who emphasized that this disease is biological.

Beyond VO2 Max – Keller on the Other Exercise Intolerant Subsets

The recent emergence of Betsy Keller demonstrates just how important it is to enroll more researchers into working on ME/CFS. In the last three years Keller has published three studies which have validated and expanded upon Workwell’s stunning exercise findings. Like Maureen Hanson, Keller has become a force of her own in this field, and we’re lucky to have her.

In this talk she shed some light on the variability we’ve seen in these studies. Her findings suggested that just about everything that can go wrong in this test does go wrong, at least with someone somewhere in the ME/CFS community. Keller’s evaluation of almost 100 patients indicated that ME/CFS patients can and do respond very differently to two-day exercise tests.

Researchers have generally focused on ME/CFS patients’ inability to reach similar levels of VO2 max or VO2 max at the anaerobic threshold on a second exercise test. Keller’s analysis indicated that these tests are important: 34% and 39% of ME/CFS patients, respectively, showed declines on the next day exercise test in their VO2 max or V02 max at the anaerobic threshold (VO2/VAT). But there’s more to the exercise problems than that.

Problems with autonomic nervous functioning (43%) and ventilation (47%) were prominent as well – plus almost a third of those tested (29%) didn’t display any abnormalities. VO2 max, then, is not the be all and end all in ME/CFS – problems exist in different facets of the energy production process in different patients.

Keller’s more intensive examination of an identical twin pair, one with and without ME/CFS, suggested that exercise probably affects many factors including inflammation, leaky gut and gut microbiome diversity. Plus increased lactate dehydrogenase (LDH) levels suggested – in line with what Fluge/Mella and the Australians are finding – a dysfunction in the pyruvate dehydrogenase (PDH) complex is present.

Keller’s and Cook’s findings suggested that the massive amount of testing done after exercise in the NIH’s Intramural study including immune and autonomic studies, brain imaging and others may reap big dividends indeed.

When Autonomic Nervous System Failure Causes Exercise Problems in ME/CFS

The Baraniuk group at Georgetown University in Washington D.C. is doing some fascinating work. Some people with POTS do quite well with exercise, but Madison Keefe of the Baraniuk group discovered that exercise can have the opposite effect in ME/CFS; it can actually induce a temporary case of POTS.

Postural orthostatic tachycardia syndrome (POTS) occurs when one’s heart rate increases abnormally rapidly upon standing.


Exercise induces temporary cases of POTS in about half of those tested

Rather remarkably, almost half of the 19 ME/CFS patients temporarily developed POTS after exercising. They probably experienced things like dizziness, heart pounding, fatigue, etc., upon standing after exercise. Autonomic nervous system testing indicated that increased sympathetic nervous system activity was probably responsible. (The ME/CFS patients who did not exhibit increased sympathetic nervous system activity didn’t come down with POTS). None of the ME/CFS patients had been diagnosed with POTS prior to the exercise test.

Exaggerated sympathetic nervous system activity, then, is yet another thing to look for in exercise studies. Because POTS simply requires measuring heart rate when going from resting to standing, it’s an easy test to do. It’s a bit surprising that we don’t see more heart rate variability measures done within exercise studies; hopefully this is the first of many to come.

  • Coming up next: the Immune System and Brain Overviews, ME/CFS Experts on the Conference and, The Future..

Thanks to the IACFS/ME for their support and to Adria and Karen for their help with housing.

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