As time has gone on, the energy production issue in chronic fatigue syndrome (ME/CFS) has become better and better documented as researchers take different slants on it.

Multiple studies, taking different slants, have found energy production problems in ME/CFS.

Take the whole body energy production tests. Workwell’s two day cardiopulmonary exercise tests (CPETs) have documented the damaging effects that exercise one day has on ME/CFS patients’ ability to produce energy the next day. Harvard pulmonologist David Systrom’s invasive CPETS have located multiple areas of deficiency (poor oxygen uptake, microcirculatory problems, reduced preload) in energy production. From Katarina Lien in Norway, to Betsy Keller in the U.S., to Vermeulen and Visser in the Netherlands, many studies suggest that fundamental problems producing energy exist. (We await the results of one of the most intriguing studies: Avindra Nath’s CPET/metabolic chamber study.)

Then there’s the whole body metabolism slant. Metabolic profiling using metabolomics has provided another way to demonstrate that something in the energy production process has gone awry.

Then there’s the cellular energy production slant. Rahim Esfandyarpour and Ron Davis’s nanoneedle tests seem to suggest that a breakdown in cellular energy production occurs when ME/CFS patient’s cells are put under stress. Missailidis and the Fisher group in Australia have identified abnormal complex activity in the mitochondria. The Newcastle group has specialized in cellular energy production – and they always seem to find intriguing and different ways to test it.

This is by no means a comprehensive overview of energy production studies in ME/CFS. The point is that problems in energy production seem to crop up in whatever compartment ME/CFS researchers have looked in.

The Study

The Gist

  • No matter how they’ve looked at it – whether using exercise tests, metabolic profiling or cellular stress tests – studies have found energy production problems in ME/CFS.
  • For the second time Cara Tomas and the Newcastle group threw ME/CFS patients cells into the Seahorse machine – and tested how well they produced energy.
  • For the second time the group got much the same results: both glycolysis (anaerobic) and the TCA cycle (aerobic) worked just fine!
  • Reduced glucose metabolism, though, suggested that people with ME/CFS were not using their most efficient energy source effectively. Their cells were, as other studies have suggested, turning to amino acids for fuel.
  • While the glycolysis and aerobic energy production systems seemed to be working fine, one aspect – the conversion of pyruvate (the outcome of glycolysis) into acetyl CoA – the starting point of the TCA cycle – appeared to be impaired. This could have quite negative consequences as the TCA cycle provides the vast majority of the ATP we rely on.
  • The fact that the group has now found similar energy problems in two very different cell types (immune/muscle cells) suggests the energy production problems in ME/CFS may be everywhere.
  • The authors proposed that the energy production problems in ME/CFS cells were likely genetic or epigenetic in nature.
  • Problems with hydrogen sulfide metabolism could play a role: a blog on that is coming up.


Cara Tomas, Julia Newton and the Newcastle group have been on a roll lately – pumping out 5 papers over the past two years. In this study, “Substrate utilisation of cultured skeletal muscle cells in patients with CFS“, Cara Tomas and colleagues dug muscle cells out of patients and then ran them through the Seahorse machine.

The Newcastle group has done this kind of analysis before on immune cells called PBMCs (peripheral blood mononuclear cell). That study found that put under stress, the immune cells were unable to produce as much energy as cells from healthy controls.

In 2015, Newton found that when stimulated, muscle cells from ME/CFS patients demonstrated impaired activation of AMPK – the protein kinase which stimulates the cells to uptake the glucose and fatty acids it needs to produce energy. Impaired stimulation of glucose uptake was found as well. The cells, then, were not getting the substrates they needed to produce energy.

The next study, though, suggested that AMPK wasn’t likely the problem – the problem was something upstream of it. This time, the group took perhaps the most energetically challenged of all cells – the muscle cells – and tweaked them in different ways while putting them through their paces in the Seahorse.

The question they attempted to answer was where the blockade in energy production occurred, and if the energy production problems they found in the immune cells extend to the muscles; i.e. are they likely body-wide?

Like many of these studies, this was a small study – just 20 people – and thus the results must be considered preliminary.


First, some background:

  1. Glycolysis results in pyruvate (and yields 2 ATP (per molecule).
  2. Pyruvate is then broken down into acetyl-CoA.
  3. Acetyl-CoA is the starting point for the citric acid or TCA (or Krebs cycle).
  4. The TCA cycle produces most of our ATP (yields 30-36 molecules of ATP in the TCA cycle).

Glycolysis was working fine.

The Seahorse is able to test both parts of our energy production cycle independently. The study suggested that the muscle cells of ME/CFS patients have problems utilizing glucose, but glycolysis was working fine; i.e. when the glycolytic cycle was given glucose, it was able to convert it into pyruvate at a good rate..

Tests of the mitochondrial respiration (cycle citric acid, TCA or the Krebs cycle – all refer to the same process) using galactose and fatty acids) suggested that it was able to punch out ATP at a good rate: it was working fine.

If glycolysis and the TCA cycle are working fine, then where was the problem?

If I got it right, the problem appeared to be in the intermediary between the two – where pyruvate – the end point of glycolysis – is transformed into acetyl-CoA – the beginning of the TCA cycle. That suggests that either the pyruvate dehydrogenase complex (PDH) – which transforms pyruvate into acetyl-CoA – is breaking down, and/or pyruvate dehydrogenase kinase (PDK) – which inhibits PDH – is acting up.

Fluge found evidence of increased PD kinase activity – which could be stopping PDH from metabolizing pyruvate to acetyl-CoA.

The possibility of a defect in the pyruvate dehydrogenase complex (PDH) brings us back to Fluge’s mammoth 2016 study, “Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome“. That study, coming from an entirely different angle, pinned the blame on the PDH complex as well. Fluge’s 300-person metabolomics study found that reductions in amino acids that fuel the TCA cycle suggested that the PDH enzyme was not converting pyruvate to Acetyl CoA.

This problem, interestingly enough – given the results of last year’s study suggesting that too much lactate is being produced during exercise in ME/CFS – would result in an accumulation of pyruvate and an overproduction of lactate. (Lactate is produced from pyruvate.)

A reduced breakdown of pyruvate – which ultimately comes from glucose – results in the increased usage of ketogenic amino acids (fats, amino acids) in the TCA cycle. (That could explain why ketogenic type diets are helpful for some people). Fluge also found increases in the expression of pyruvate dehydrogenase kinases and the SIRT4 enzyme – both of which shut down PDH.

PDK, interestingly, ramps up its activity during times of starvation in order to limit energy usage. It’s intriguing how many different time concepts like ‘starvation, hibernation and hypometabolism” have been used in ME/CFS.

Lastly, the authors asserted that the study results indicate that the problems with the mitochondria are likely either genetic or epigenetic in nature.


Twenty years of research from ME Research UK!

If I read it right, this study, then, suggests two major problems are present: ME/CFS patients’ muscles cells are not utilizing glucose well, and there’s a problem converting pyruvate to Acetyl CoA.

We’ve heard about the problems with glucose before. Glucose – the quickest, most efficient energy source – is apparently being replaced, to some extent, by less efficient amino acids and fats as an energy substrate.

If pyruvate is not being properly metabolized to acteyl CoA, it will show up in the form of increased lactate levels – which a study by the Fluge group found last year.

Since the Newcastle group has found these problems in both the immune and muscle cells (and those cells are nothing like each other) this study suggests these energy production problems likely show up in many cells and is body-wide.

So, we have yet more evidence – albeit in a small study – of impaired energy production. While we can’t tie the results of all of the energy studies together yet and say, “this is the source” of them, it’s remarkable how many different ways it’s been shown.

On that note, a “new” possibility has recently popped up. It’s actually not a new possibility – in fact, it may be one of the first explanations to show up in the ME/CFS literature involving the mitochondria. In “Hypothesis: Chronic Fatigue Syndrome, Mitochondrial Hypo-function, and Hydrogen Sulfide”, in 2007 Marian Lemle proposed that altered levels of hydrogen sulfide (H2S) could be involved in the energy production problems in ME/CFS. Her thesis is now being investigated by Bindu Paul, a Johns Hopkins researcher. Marian pointed out back then that alterations in H2S can increase blood lactate concentration and altered lactate/pyruvate ratios – resulting in more anaerobic glycolysis. (A blog on H2S and ME/CFS is coming up.)

It’s great to have these creative researchers at work, but we should note that this work doesn’t come for free, or cheaply, and this mitochondrial work was entirely community-supported, in this case by ME Research UK, which is celebrating its 20th year of funding ME research. Let’s celebrate them and thank them for funding this intriguing study and all the others.


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