- Resource Type
- Report or Study
(As metabolomics studies providing evidence of severe energy depletion and mitochondrial dysfunction in chronic fatigue syndrome (ME/CFS) pour out, Hip examines the work of a pioneer in the mitochondrial and ME/CFS field. Thanks for allowing Health Rising to post) this easy to understand post on the mitochondria and ME/CFS)
The ME/CFS Energy Metabolism Studies of Dr. Sarah Myhill et al.
Dr. Sarah Myhill is a GP with a lot of research interest and expertise in treating ME/CFS. Norman E. Booth is a physicist and molecular biologist. John McLaren-Howard is cofounder of Biolab Medical Unit, and medical director of Acumen Labs, UK.
• The experimental results of these studies strongly implicate mitochondrial dysfunction as an intermediate cause of ME/CFS symptoms (by "intermediate," I think the authors mean not the primary cause of ME/CFS, which may for example be viral and/or autoimmune, but an intermediate pathophysiology that is induced by the primary cause).
• The studies used the "ATP Profiles" test (Acumen Laboratory, UK) to measure the efficiency of five metabolic pathways involved in energy production. The "ATP Profiles" test provides five numerical figures that indicate the functional efficiency of each of the five energy pathways.
Using this "ATP Profiles" test in their studies, the authors found that almost all ME/CFS patients in their cohorts had defective energy production (the studies examined ~200 ME/CFS patients). However, out of the five metabolic pathways, each patient had their own particular pathways that were at fault (ie, running at low efficiency), and their own particular pathways that were working fine (running at normal efficiency). So all patients had defective energy production, but there were patient subsets according to which particular energy metabolism pathways were dysfunctional.
• Because the studies discovered that defects in energy metabolism are not found in just in one pathway, but found in up to five different pathways, the authors combined the individual efficiency figures for each of the five pathways into one single efficiency figure, which they call the Mitochondrial Energy Score (MES). The MES is thus a single numerical value that gives the overall efficiency of a patient's energy production.
• The authors found there is a high degree of correlation between the Mitochondrial Energy Score and the degree of severity of ME/CFS (severity as measured on the Bell scale).
• Furthermore, the Mitochondrial Energy Score value was able to successfully distinguish between ME/CFS patients and healthy controls in nearly all cases. So the Mitochondrial Energy Score could be a good potential biomarker for ME/CFS (although the authors do not claim a low MES is unique to ME/CFS, because there are other neurological illnesses and metabolic syndromes which are also associated with mitochondrial dysfunction).
• Most impressively, the authors pinpoint what may be the physiological mechanism behind post-exertional malaise (PEM). Briefly, they suggest PEM occurs when adenosine triphosphate (ATP) molecules, whose role it is to convey energy, inadvertently in effect get flushed out of the body in the urine, via a particular set of metabolic circumstances; this results in a temporary shortage of ATP molecules, and a temporary inability to transport energy in the cell — a situation which they posit causes PEM. Full explanation coming up next.
Sarah Myhill et al's Theory of PEM
Rather than jumping straight into the 5 energy pathways that were found at fault in ME/CFS, we are going to start with Myhill et al's biochemical explanation of how PEM arises, as this is quite easy to understand, and makes a nice introduction the studies.
So we begin with the studies' findings that ME/CFS involves a poor, low-efficiency energy metabolism. There are knock-on effects arising from this poor energy metabolism — knock-on effects that occur in periods of exertion when the energy demands of the body are high, and the blocked energy metabolism is thus overtaxed and put under stress. Dr Myhill explains:
In other words, Dr Myhill is saying that delayed fatigue and presumably post-exertional malaise arise when some of the ADP molecules, which are normally very quickly recycled back to ATP, instead get converted to ATP in a desperate attempt to harvest energy; and because ATP is not easily recycled, this ATP is flushed right out of the body, thereby causing a permanent loss of the ADP molecules that the ATM was derived from.
Problems arise when the system is stressed. If the CFS sufferer asks for energy faster than he can supply it (and actually most CFS sufferers are doing this most of the time!), ATP is converted to ADP faster than it can be recycled.
This means there is a build up of ADP. Some ADP is inevitably shunted into adenosine monophosphate (AMP). But this creates a real problem, indeed a metabolic disaster, because AMP, largely speaking, cannot be recycled and is lost in urine.
Indeed this is the biological basis of poor stamina. One can only go at the rate at which mitochondria can produce ATP. If mitochondria go slow, stamina is poor.
If ATP levels drop as a result of leakage of AMP, the body then has to make brand new ATP. ATP can be made very quickly from a sugar D-ribose, but D-ribose is only slowly made from glucose (via the pentose phosphate shunt for those clever biochemists out there!). This takes anything from one to four days. So this is the biological basis for delayed fatigue.
Source: CFS - The Central Cause: Mitochondrial Failure
So then you get an acute shortage of ADP molecules, which is a major problem, because ATP/ADP recycling is the main basis of the body's energy creation and distributing system, responsible for carrying more than 90% of our cellular energy.
As a consequence of this shortage, more of these ATP/ADP molecules then have to be manufactured by the body from scratch, to replace the lost ATP/ADP molecules. And efficient energy distribution can only be resumed once these lost molecules are manufactured. But it takes 1 to 4 days for the body to rebuild its stock of ATP/ADP molecules, as it takes a lot longer to rebuild the ATP molecule from scratch (this called de novo synthesis), rather than simply making ATP by recycling ADP molecules.
Dr Myhill et al. think this 1 to 4 days of novo synthesis of ATP may explain the PEM period: you get PEM and delayed fatigue for several days after physical exertion, as your body struggles to rebuild its stock of ATP and ADP molecules.
Note: to be clear, when Dr. Myhill is referring to a shortage of ATP/ADP molecules during the PEM period, this not so much a shortage of energy itself (although energy supply may also be poor), but rather an acute shortage of the ATP/ADP molecules that carry and convey the energy generated in the mitochondria.
This is analogous to saying there is not so much a shortage of electricity, but rather a shortage of rechargeable batteries for storing and carrying that electricity to where it is needed. The ATP/ADP molecules are analogous to a rechargeable battery: ATP is like a fully charged battery, and ADP likes an empty battery. ADP can be quickly recharged back to ATP at any time, using energy from the mitochondria.
Dr. Myhill is saying that PEM results when the body inadvertently dumps many of its ATP/ADP rechargeable batteries, and so then the body has too few batteries to distribute the energy made by the mitochondria. You only get over the PEM period when your body makes more rechargeable batteries (makes more ATP/ADP molecules).
So this is a compelling theory of how PEM arises (and I believe it is the first theory proposed to explain the mystery of PEM and delayed fatigue).
I was thinking that Dr. Myhill's ATP/ADP molecule restocking theory of PEM suggests that D-ribose supplementation specifically during the PEM period might help mitigate PEM, since Myhill points out that the ATP molecule is easily synthesized from D-ribose (by de novo synthesis). So taking D-ribose specifically during PEM may help you to more quickly rebuild your stock of ATP molecules.
Dr. Myhill then goes on to explain how in ME/CFS high levels of lactic acid arise during physical exertion, as a direct result of this ATP molecule shortage:
So Myhill et al. are saying that as a consequence of this shortage of ATP/ADP molecules (the rechargeable batteries), the body desperately tries to manufacture new ATP molecules (make more rechargeable batteries) by any route it can. One route is to manufacture ATP via the conversion of glucose to lactic acid (anaerobic glycolysis), which takes place in the cell cytosol rather than the mitochondria. But by making ATP in this way, you get a build up of lactic acid.
However there is another problem. If the body is very short of ATP, it can make a very small amount of ATP directly from glucose by converting it into lactic acid.
This is exactly what many CFS sufferers do and indeed we know that CFS sufferers readily switch into anaerobic metabolism. However this results in two serious problems — lactic acid quickly builds up especially in muscles to cause pain, heaviness, aching and soreness ("lactic acid burn"), secondly no glucose is available in order to make D-ribose! So new ATP cannot be easily made when you are really run down. Recovery takes days!
When mitochondria function well, as the person rests following exertion, lactic acid is quickly converted back to glucose (via-pyruvate) and the lactic burn disappears. But this is an energy requiring process! Glucose to lactic acid produces two molecules of ATP for the body to use, but the reverse process requires six molecules of ATP. If there is no ATP available, and this is of course what happens as mitochondria fail, then the lactic acid may persist for many minutes, or indeed hours causing great pain. (for the biochemists, this reverse process takes place in the liver and is called the Cori cycle).
Source: CFS - The Central Cause: Mitochondrial Failure
So this would explain why ME/CFS patients generate far higher levels of lactic acid during physical exertion: it's the result of the desperate attempt to make more ATP, which the body needs in order to convey the energy generated by the mitochondria.
This lactic acid build-up then further compounds the energy shortage problem of PEM, because clearing lactic acid by converting it back to glucose, requires considerably more energy than was originally gained from the conversion of glucose to lactic acid. (Glucose to lactic acid yields two molecules of ATP for the body to use, but the reverse process uses up six molecules of ATP).
Obtaining energy by the conversion of glucose to lactic acid is an act of desperation by the body: it's like being desperate for money and going to a loan shark, only to find that you have to pay back a lot more than you were originally lent.
So Myhill et al. are theorizing that the production of lactic acid further contributes to the energy shortage issue that we know as PEM.
Incidentally, the idea that lactic acid build up further exacerbates PEM in this way nicely ties up with the fact that nearly all the "PEM Buster" supplements (which members of this forum have found significantly mitigate PEM) appear to reduce lactic acid. This seems to support the idea that lactic acid build up is part of the problem in PEM.
In summary: Myhill et al are theorizing that PEM may be due to an acute shortage of ATP/ADP molecules (which were dumped out of the body in the urine through the AMP route), which is then further compounded by the body desperately lending energy from the lactic acid loan shark.
So a combination of D-ribose (to help restock the body with ATP molecules) plus some of these PEM Buster supplements (to neutralize lactic acid) might work for combating PEM.
The Dysfunctional Energy Metabolism at the Root of ME/CFS
Let's now delve into the five energy pathways whose efficiencies are measured by the "ATP Profiles" test, and which were found to be poorly functioning in ME/CFS.
These five energy metabolism pathways are as follows:
(1) ATP Concentration = the quantity of ATP present in the cell
This one is very straightforward: ATP is created in the mitochondria (recycled from ADP), and created in the cell cytosol via glycolysis. This ATP then supplies energy to the cell. Mitochondria supply around 90% of the cells ATP energy needs; whereas glycolysis only supplies around 10%.
The ATP Concentration measured in the "ATP Profiles" test is simply the total amount of ATP molecules present in the cell.
(2) ATP Ratio = the fraction of ATP in the cell that is complexed with magnesium
One study found ME/CFS patients have low levels of intracellular magnesium, which may cause a shortage of magnesium for ATP to bond to, and thereby reduce the amount of ATP in the cell available to supply energy.
I wonder if this may in part explain why magnesium injections or high dose transdermal magnesium cream has been found helpful in ME/CFS. Presumably, though, such magnesium treatment might only be useful for ME/CFS patients who have a poor ATP Ratio, as measured by the "ATP Profiles" test.
Note that if you are going to try magnesium injections or high dose transdermal magnesium cream, it might be an idea to also take cofactors that promote the absorption of magnesium into cells, such as: vitamin B6 and vitamin B1 (see this and subsequent posts).
(3) Oxidative phosphorylation = efficiency of oxidative phosphorylation
Oxidative phosphorylation is the mitochondrial process by which ADP is recycled back to ATP. This recycling is achieved by adding phosphate to the adenosine diphosphate (ADP) molecule, which has two phosphates, to convert it to adenosine triphosphate (ATP), which has three phosphates.
Myhill et al found that around half the ME/CFS patients in their studies had oxidative phosphorylation running normally (these they labeled Group A patients), but the other half of patients had their oxidative phosphorylation partially blocked and running at low efficiency (these they labeled Group B patients).
In ME/CFS patients whose oxidative phosphorylation is running normally (Group A), they found cellular metabolism uses increased glycolysis to partially compensate for the overall energy metabolism dysfunction.
Whereas for patients whose oxidative phosphorylation was partially blocked (Group B), these patients use an alternative route to increased glycolysis, most likely the adenylate kinase reaction in which two molecules of ADP combine to make one of ATP and one of AMP. This creation of AMP is the same process detailed earlier, in which exertion led to the loss of ATP/ADP molecules via dumping AMP in the urine, thereby creating PEM. Ref: Myhill 2013.
In Myhill 2012 the authors state:
Note that co-enzyme Q10 is a vital factor in oxidative phosphorylation, and deficiency in Q10 may cause oxidative phosphorylation to go slow.
This division into 2 distinct groups, A and B, appears to correlate with the 2 groups observed in some exercise studies.
Recycling by Group A patients of the lactate generated by glycolysis into glucose and glycogen takes place on a shorter time scale, but Group A patients will suffer from increased acidosis due to build-up of H+ ions from ATP hydrolysis which are not recycled by the ETC, and will also exhibit excess lactate in the blood.
Group A patients will have large PCr [creatine phosphate] depletion, excess lactate production and high acidosis (depressed pH). Group B patients will have low PCr depletion (the shuttle is not needed for the ADK reaction), no excess lactate production and less acidosis for the same work load.
For repeat exercise tests patients of Group B will have great difficulty in reaching the same maximal voluntary contraction not because of the behavioral reason of exercise avoidance, but because the lost substrate has not been replaced. These predictions are close to what is observed in this recent exercise study .
(4) Translocator Protein Out = efficiency of ADP transport out from the cell
One job of translocator protein, which is located on the mitochondrial membrane, is to transport ADP in the cell across the mitochondrial membrane, and into the mitochondrion, for recycling back to ATP.
(5) Translocator Protein In = efficiency of ATP transport into the cell
Dr. Myhill says that translocator protein could be malfunctioning as a result of xenobiotic stress (e.g. organochlorine or organophosphate pesticide exposure), poor antioxidants status (lipid peroxides), and various other factors. See: Translocator protein studies - DoctorMyhill for a list of factors that can disrupt translocator protein.
Out of the five energy metabolism pathways, Translocator Protein In (TL IN) is unusual, as in some ME/CFS patients its efficiency is actually higher than it is for all of the control group. Thus some ME/CFS patients appear to be transporting super-normal amounts of ATP from their mitochondria into the cell cytosol. In Myhill 2012 they say that these super-normal values of TL IN are:
Note that the Krebs cycle substrates are: succinate, glutamate, malate, pyruvate and fatty acids.
most likely due to below normal ATP levels in the mitochondria due to shortage of substrate, either the well-known substrates of the Krebs cycle or those of the ETC, principally ADP and inorganic phosphate, Pi, but also the essential co-factors CoQ10, reduced Niacinamide (NADH) and Mg.
In Myhill 2012 they state:
Viruses, Autoimmunity and the Translocator Protein
Clearly, the partial blocking of the TL sites is a very important aspect of the mitochondrial dysfunction and this has not been considered in any other study.
One of us (JMH) is making further studies of TL function and has found chemical blocking in those cases with subnormal values. Possible sources of blocking agents are byproducts of viral or bacterial pathogens, cellular debris due to oxidative damage, and some environmental chemicals. Results from molecular level fluorescence microscopy, and the identification of the blocking agents by Micro Raman Spectroscopy and Fourier Transform Infrared Spectroscopy, will be the subject of a further paper.
I came across a very interesting connection between coxsackievirus B, autoimmunity and translocator protein: this study found autoantibodies that target and disable translocator protein in patients with myocarditis and dilated cardiomyopathy (DCM), which they then reproduced in a murine model infected with coxsackievirus B3. This seems very significant, because the chronic infections in coxsackievirus B myocarditis and dilated cardiomyopathy are very similar to the chronic coxsackievirus B infections of ME/CFS. The study authors said:
So they are proposing a molecular mimicry-type autoimmunity, where antibodies that target the virus VP protein also, unfortunately, target the translocator protein — thus in fighting the virus, the immune system antibodies inadvertently attack the crucial translocator protein on mitochondria. And indeed, it is known that energy metabolism in myocarditis and dilated cardiomyopathy is running at low efficiency, due to translocator protein dysfunction. The same autoimmune-mediated disruptions to translocator protein could thus also be happening in ME/CFS.
We were able to identify autoantibodies against the adenine nucleotide translocator [another name for translocator protein] in the sera of patients suffering from myocarditis and DCM .... These antibodies show cross-reactivity to the VP protein of Coxsackie B3 virus known to induce myocarditis in humans and animals.
As long ago as 1985, ME/CFS researchers Behan et al thought something like may be the case in ME/CFS, when they suggested that:
Anti-mitochondrial autoantibodies of various sorts have been found in a number of diseases, including lupus, Sjögren’s, myocarditis, cardiomyopathy, tuberculosis and leprosy. See: Anti-mitochondrial antibody - Wikipedia.
an autoantibody, such as the anti-mitochondrial antibody recently identified in patients with viral myocarditis, might be involved
If ME/CFS does indeed involve an energy metabolism dysfunction caused by mitochondrial autoantibodies, and if those autoantibodies do indeed derive from an autoimmune state triggered by viral infection, that would neatly tie together and explain three known features of ME/CFS pathophysiology:
- the fact that ME/CFS is associated with infection from certain viruses, particularly coxsackievirus B;
- the fact that ME/CFS likely involves autoimmunity,
- the fact that energy metabolism appears to be dysfunctional in ME/CFS. A coxsackievirus B-triggered translocator protein autoantibody could explain all these features.
Perhaps that could be one reason why supplements like fish oil (especially high EPA fish oil such as VegEPA®) which affect cellular membranes benefit some ME/CFS patients.
Study Results: Defects in 5 Energy Metabolism Pathways in ME/CFS
For the 71 ME/CFS patients in the Myhill 2009 study, figure 2 below shows how their five metabolic energy pathways (labeled A to E) were functioning in terms of efficiency, as determined by the "ATP Profiles" test.
If you glance at the second column, you can see that the blue bars, which represent ME/CFS patients' energy pathway efficiencies, are generally lower down (= less efficient) on the vertical axis of energy efficiency, compared to the gray bars in the third column, which represent the energy pathway efficiencies of the healthy controls.
This shows that these 5 energy pathways in ME/CFS patients are generally functioning at a reduced output compared to healthy people. Similar low energy pathway efficiencies were found in the 138 ME/CFS patients of the Myhill 2012 study.
The Five Energy Pathway Efficiencies of ME/CFS Patients and Health Controls
Figure 2 from Myhill 2009
The Mitochondrial Energy Score (MES)
As the above figure 2 shows, defects in ME/CFS patients' energy metabolism are found not just in one area, but in up to five different energy pathways. So in the study, the authors combined the efficiency figures for each of the five energy pathways into one overall efficiency figure, called the Mitochondrial Energy Score (MES). The Mitochondrial Energy Score thus provides a single numerical value that indicates the overall efficiency of energy production.
In the Myhill 2009 study, in figure 4a shown below, they plot a graph of the Mitochondrial Energy Score against the severity of ME/CFS, as measured by the Bell scale.
Mitochondrial Energy Score vs ME/CFS Severity
Figure 4a from Myhiil 2009
It is immediately apparent from this graph that the Mitochondrial Energy Score clearly separates ME/CFS patients from healthy controls in almost all cases; and furthermore, that the MES strongly correlates with the severity of ME/CFS.
Some References and Further Reading
Sarah Myhill, Norman E. Booth and John McLaren-Howard's three studies on mitochondrial failure in ME/CFS:
- Chronic fatigue syndrome and mitochondrial dysfunction (2009)
- Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (2012)
- Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit (2013)
- Diagnosis and Treatment of Chronic Fatigue Syndrome: Mitochondria, Not Hypochondria (Diagnosing & Treating)
A Dr Myhill video explaining the mitochondrial dysfunctions in ME/CFS, and detailing the "ATP Profiles" test:
An example of the results of the "ATP profiles" test can be seen in this post, from a forum member who took this test.
A summary of Myhill, Booth and McLaren-Howard's mitochondrial dysfunction ME/CFS research, testing and treatment can be found on www.me-ireland.com.[/fright]