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The ME/CFS Energy Metabolism Studies of Myhill, Booth and McLaren-Howard
EDIT 2019: A replication study by Tomas et al examining the validity of the Mitochondrial Energy Score (MES) blood testing protocol used by Acumen labs found no difference between ME/CFS patients and healthy controls. The study concluded:
The Myhill group's response to this replication study is found here.
With recent metabolomic studies from Fluge and Mella as well as Robert Naviaux et al finding defects in the energy metabolism of ME/CFS patients, perhaps now we should more closely examine the three very incisive studies of Dr Sarah Myhill, Norman E. Booth and John McLaren-Howard (published in 2009, 2012 and 2013) on the dysfunctional energy metabolism of ME/CFS.
The research of Myhill, Booth and McLaren-Howard on defective energy production in ME/CFS has not been covered in any great depth on these forums, particularly not on the theory side. Hopefully we can rectify that in this thread.
Summary Points
• 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 processes involved in energy production. The "ATP Profiles" test provides five numerical figures that indicate the functional efficiency of each of the five energy metabolism processes.
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 energy metabolism processes, each patient had their own particular processes that were at fault (ie, running at low efficiency), and their own particular processes that were working fine (running at normal efficiency). So all ME/CFS patients had defective energy production, but there were patient subsets according to which particular energy metabolism processes were dysfunctional.
• Because the studies discovered that defects in energy metabolism are not found in just one process, but found in up to five different processes, the authors combined the individual efficiency figures for each of the five processes 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).
• The authors do not mention this in their studies, but other research I came across indicates that defects in two energy metabolism processes found at fault in some ME/CFS patients (namely the two translocator protein energy metabolism processes) could be caused by an autoantibody that targets and disables this translocator protein (by which we mean the ANT protein). This ANT autoantibody appears to be triggered by coxsackievirus B, as the autoantibody has been found in CVB myocarditis. As far as I can see, this virally-associated autoantibody may well in part explain how viral infection causes ME/CFS.
• 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 get broken down and ultimately 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 thus a temporary inability to transport energy in the cell — a situation which they posit causes PEM. Full explanation coming up next.
The Myhill, Booth and McLaren-Howard Theory of PEM
Rather than jumping straight into the 5 energy metabolism processes that were found at fault in ME/CFS, we are going to start with Myhill, Booth and McLaren-Howard's biochemical explanation of how PEM arises, as this is quite easy to understand, and makes a nice introduction to 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. On her website, Dr Sarah Myhill explains:
In other words, Dr Myhill is saying that because of the poor energy metabolism and mitochondrial inefficiencies found in ME/CFS patients, during physical exercise, there is an acute shortage of energy and the mitochondria cannot recycle ADP back to ATP fast enough, so there is a build up of ADP molecules.
In a desperate attempt to harvest more energy, some of the ADP molecules, which are normally recycled back to ATP, instead get converted to AMP (this conversion to AMP occurs by what is known as the adenylate kinase reaction, in which two molecules of ADP combine to make one of ATP and one of AMP).
However, because AMP is not easily recycled, this AMP is flushed right out of the body, thereby causing a permanent loss of the ADP molecules that the AMP was derived from.
(The exact way AMP is flushed from the body is this: AMP is first changed into inosine monophosphate plus ammonia, the inosine monophosphate is then degraded to inosine, and then to hypoxanthine, then to xanthine, and finally eliminated in the urine as uric acid. Ref: Myhill 2012).
So you get a temporary acute shortage of ATP and ADP molecules, which is major problem, because ATP/ADP recycling is the main basis of the body's energy distributing system, responsible for carrying more than 90% of our cellular energy. So now your body is short of energy, simply because you do not have the means to transport it: the ATP and ADP molecules. The theory states that this temporary shortage of ATP and ADP molecules, which are needed to transport the energy from the mitochondria into the cell, causes PEM.
As a consequence of this temporary shortage, more of these ATP/ADP molecules have to be manufactured by the body from scratch, to replace the lost 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 manufacture the ATP molecule from scratch (this called de novo synthesis), rather than the more usual and easier process of creating ATP by recycling ADP.
Myhill, Booth and McLaren-Howard think this 1 to 4 days of novo synthesis of ATP may explain the PEM period: you get PEM for several days after physical exertion due to the acute shortage of ATP/ADP molecules; and you remain in PEM until your body finishes rebuilding its stock of ATP and ADP molecules.
Note: to be clear, when Myhill, Booth and McLaren-Howard are referring to a shortage of ATP/ADP molecules during the PEM period, this not so much a shortage of energy in the mitochondria (although mitochondrial energy supply may be poor as well), but rather an acute temporary shortage of ATP/ADP molecules with which convey the energy generated in the mitochondria to where it is needed in the cell. In other words, PEM is an acute problem of transport of energy, where you temporarily do not have enough ATP/ADP energy transportation molecules.
If you want an analogy: imagine that the mitochondria are like oil refineries making energy in the form of gasoline; and imagine that the ATP molecules are like gasoline trucks filled with gasoline and transporting this fuel to where it is needed, and that the ADP molecules are like empty gasoline trucks that have delivered their fuel, and are returning back to the refinery to be refilled again.
Myhill, Booth and McLaren-Howard are saying PEM arises when the body inadvertently temporarily loses many of its gasoline trucks, so it does not have enough trucks to distribute the fuel energy to where it is need. You only get over the PEM period when your body manufactures some brand new gasoline trucks to replace the lost ones (manufactures more ATP/ADP molecules), so that you can start efficiency delivering the fuel energy again.
So this is a compelling theory of how PEM may arise.
I was thinking that Myhill, Booth and McLaren-Howard's ATP/ADP molecule restocking theory of PEM suggests that D-ribose supplementation specifically during the PEM period might help mitigate PEM, since they point 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 Sarah 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, Booth and McLaren-Howard are saying that as a consequence of this shortage of ATP/ADP molecules (the gasoline trucks), the body desperately tries to manufacture new ATP molecules (manufacture more gasoline trucks) by any route it can. And one route of manufacturing ATP is 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.
So this would explain why ME/CFS patients generate far higher levels of lactic acid during physical exertion: it is just a 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 to clear lactic acid by converting it back to glucose, it 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 a bit of 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, Booth and McLaren-Howard 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, Booth and McLaren-Howard are theorizing that PEM may be due to an acute shortage of ATP/ADP molecules (due to these molecules being broken down and ultimately dumped out of the body in the urine), 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 metabolism processes whose efficiencies are measured by the "ATP Profiles" test, and which were found to be poorly functioning in ME/CFS.
These five energy metabolism processes 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 cell's 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.
In terms of the amount of ATP molecules present in the cells of ME/CFS patients, the Myhill 2009 study found ME/CFS patients only have around 60% of the ATP of healthy controls. Thus there is a major ATP energy shortage in the cells of ME/CFS patients.
(You can derive this 60% figure from Figure 2A of the study, where you see that on average, healthy controls have ATP concentrations of around 2 fmol per cell, whereas on average ME/CFS patients have around 1.2 fmol per cell, with some patients having as little as 0.9 fmol per cell.)
(2) ATP Ratio = the fraction of ATP in the cell that is complexed with magnesium
The majority of ATP molecules present in cells are bonded onto magnesium ions, to create a complex known as Mg-ATP. This bonding to magnesium is necessary in order for ATP to yield its energy; ATP molecules that are not bound to magnesium are not able to liberate the energy they carry. Thus an important factor in energy metabolism efficiency is the percentage of ATP in the cell that is bonded to magnesium, as only this percentage can supply energy. This percentage is given by the ATP Ratio. The ATP Ratio is also an indication of the amount of magnesium in the cell.
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 post and the 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, Booth and McLaren-Howard found that around half the ME/CFS patients in their studies had oxidative phosphorylation running normally (these they labelled Group A patients); but the other half of patients had their oxidative phosphorylation partially blocked and running at low efficiency (these they labelled Group B patients).
In ME/CFS patients whose oxidative phosphorylation is running normally (Group A), they found cellular metabolism uses increased anaerobic 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 adenylate kinase reaction is the same process which it is theorized leads to PEM, via the break down and loss of the energy-carrying ATP/ADP molecules. Ref: Myhill 2013.
D-ribose may be an especially important nutrient for Group B patients. 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.
(4) Translocator Protein Out = efficiency of ADP transport out from the cell
One job of translocator protein (ANT protein), which is located on the inner mitochondrial membrane, is to transport ADP in the cell across the inner mitochondrial membrane, and into the mitochondrion, for recycling back to ATP.
(5) Translocator Protein In = efficiency of ATP transport into the cell
The other job of translocator protein (ANT protein) is to transport the energy-carrying ATP molecules created in the mitochondria (from recycled ADP) across the inner mitochondrial membrane and into the cell, where their energy is used for cellular functioning. The efficiency of this ATP transport process across the mitochondrial membrane is another important factor in the efficiency mitochondrial energy production.
Dr Myhill says that translocator protein (ANT) 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 processes, 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:
In Myhill 2012 they state:
Note that in the Myhill studies, when they refer to the "translocator protein", they actually mean the adenine nucleotide translocator (ANT), also called the ATP-ADP-translocator. ANT is a protein located on the inner mitochondrial membrane.
It is confusing that Myhill et al to refer to ANT as the "translocator protein", because the term "translocator protein" normally refers to a different protein called TSPO, which is located on the outer mitochondrial membrane. Both ANT and TSPO work in conjunction to ferry ATP out of the mitochondria; but they are two separate proteins.
Could Enterovirus-Triggered Autoantibodies Be Blocking The Mitochondrial Translocator Protein in ME/CFS?
I came across an interesting connection between coxsackievirus B, autoimmunity and the mitochondrial adenine nucleotide translocator (ANT): this study found autoantibodies which target and disable ANT in patients with viral myocarditis and dilated cardiomyopathy, 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 found in ME/CFS. The study authors said:
The authors are proposing a molecular mimicry-type autoimmunity, where antibodies that target the virus VP protein also unfortunately cross-reactive to ANT — thus in fighting the virus, the immune system antibodies inadvertently attack and block the crucial ANT protein on mitochondria.
It is known that energy metabolism in myocarditis and dilated cardiomyopathy is running at low efficiency, due to ANT dysfunction. The same autoimmune-mediated disruptions to ANT could thus also be happening in ME/CFS.
As long ago as 1985, ME/CFS researcher Prof Peter Behan stated in this paper that he thought something like may be the case in ME/CFS:
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.
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:
(i) the fact that ME/CFS is associated with infection from certain viruses, particularly coxsackievirus B
(ii) the fact that ME/CFS likely involves autoimmunity
(iii) the fact that energy metabolism appears to be dysfunctional in ME/CFS
A coxsackievirus B-triggered ANT autoantibody could explain all these features.
More detailed info on Prof Peter Behan's ANT protein autoantibody theory of ME/CFS is found in this thread.
Study Results: Defects in 5 Energy Metabolism Processes in ME/CFS
For the 71 ME/CFS patients in the Myhill 2009 study, figure 2 below shows how their five energy metabolism processes (labelled A to E) were operating 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 metabolism process 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 metabolism process efficiencies of the healthy controls.
This shows that these 5 energy metabolism processes in ME/CFS patients are generally operating at a reduced output compared to healthy people. Similar low energy metabolism process efficiencies were found in the 138 ME/CFS patients of the Myhill 2012 study.
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 processes of energy metabolism. So in the study, the authors combined the efficiency figures for each of the five energy metabolism processes 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.
It is apparent from this graph that the Mitochondrial Energy Score roughly separates ME/CFS patients from healthy controls; and furthermore, as the MES roughly 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:
A summary of Myhill, Booth and McLaren-Howard's energy metabolism defect research can be found on Dr Sarah Myhill's website:
Video in which Dr Sarah Myhill explains the mitochondrial dysfunctions in ME/CFS, and (at timecode 20:53) details 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.
EDIT 2019: A replication study by Tomas et al examining the validity of the Mitochondrial Energy Score (MES) blood testing protocol used by Acumen labs found no difference between ME/CFS patients and healthy controls. The study concluded:
This Tomas study was a long-awaited replication study of the Myhill group work. The ME Association who funded this replication study have an article on it here.
The Myhill group's response to this replication study is found here.
With recent metabolomic studies from Fluge and Mella as well as Robert Naviaux et al finding defects in the energy metabolism of ME/CFS patients, perhaps now we should more closely examine the three very incisive studies of Dr Sarah Myhill, Norman E. Booth and John McLaren-Howard (published in 2009, 2012 and 2013) on the dysfunctional energy metabolism of ME/CFS.
The research of Myhill, Booth and McLaren-Howard on defective energy production in ME/CFS has not been covered in any great depth on these forums, particularly not on the theory side. Hopefully we can rectify that in this thread.
Dr Sarah Myhill is a GP with a great deal of research interest and expertise in treating ME/CFS.
Dr Norman E. Booth is a retired academic physicist with two family members who have been affected by ME/CFS.
Dr John McLaren-Howard is cofounder of Biolab Medical Unit, and medical director of Acumen Labs, UK.
Summary Points
• 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 processes involved in energy production. The "ATP Profiles" test provides five numerical figures that indicate the functional efficiency of each of the five energy metabolism processes.
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 energy metabolism processes, each patient had their own particular processes that were at fault (ie, running at low efficiency), and their own particular processes that were working fine (running at normal efficiency). So all ME/CFS patients had defective energy production, but there were patient subsets according to which particular energy metabolism processes were dysfunctional.
• Because the studies discovered that defects in energy metabolism are not found in just one process, but found in up to five different processes, the authors combined the individual efficiency figures for each of the five processes 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).
• The authors do not mention this in their studies, but other research I came across indicates that defects in two energy metabolism processes found at fault in some ME/CFS patients (namely the two translocator protein energy metabolism processes) could be caused by an autoantibody that targets and disables this translocator protein (by which we mean the ANT protein). This ANT autoantibody appears to be triggered by coxsackievirus B, as the autoantibody has been found in CVB myocarditis. As far as I can see, this virally-associated autoantibody may well in part explain how viral infection causes ME/CFS.
• 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 get broken down and ultimately 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 thus a temporary inability to transport energy in the cell — a situation which they posit causes PEM. Full explanation coming up next.
The Myhill, Booth and McLaren-Howard Theory of PEM
Rather than jumping straight into the 5 energy metabolism processes that were found at fault in ME/CFS, we are going to start with Myhill, Booth and McLaren-Howard's biochemical explanation of how PEM arises, as this is quite easy to understand, and makes a nice introduction to 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. On her website, Dr Sarah Myhill explains:
In other words, Dr Myhill is saying that because of the poor energy metabolism and mitochondrial inefficiencies found in ME/CFS patients, during physical exercise, there is an acute shortage of energy and the mitochondria cannot recycle ADP back to ATP fast enough, so there is a build up of ADP molecules.
In a desperate attempt to harvest more energy, some of the ADP molecules, which are normally recycled back to ATP, instead get converted to AMP (this conversion to AMP occurs by what is known as the adenylate kinase reaction, in which two molecules of ADP combine to make one of ATP and one of AMP).
However, because AMP is not easily recycled, this AMP is flushed right out of the body, thereby causing a permanent loss of the ADP molecules that the AMP was derived from.
(The exact way AMP is flushed from the body is this: AMP is first changed into inosine monophosphate plus ammonia, the inosine monophosphate is then degraded to inosine, and then to hypoxanthine, then to xanthine, and finally eliminated in the urine as uric acid. Ref: Myhill 2012).
So you get a temporary acute shortage of ATP and ADP molecules, which is major problem, because ATP/ADP recycling is the main basis of the body's energy distributing system, responsible for carrying more than 90% of our cellular energy. So now your body is short of energy, simply because you do not have the means to transport it: the ATP and ADP molecules. The theory states that this temporary shortage of ATP and ADP molecules, which are needed to transport the energy from the mitochondria into the cell, causes PEM.
As a consequence of this temporary shortage, more of these ATP/ADP molecules have to be manufactured by the body from scratch, to replace the lost 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 manufacture the ATP molecule from scratch (this called de novo synthesis), rather than the more usual and easier process of creating ATP by recycling ADP.
Myhill, Booth and McLaren-Howard think this 1 to 4 days of novo synthesis of ATP may explain the PEM period: you get PEM for several days after physical exertion due to the acute shortage of ATP/ADP molecules; and you remain in PEM until your body finishes rebuilding its stock of ATP and ADP molecules.
Note: to be clear, when Myhill, Booth and McLaren-Howard are referring to a shortage of ATP/ADP molecules during the PEM period, this not so much a shortage of energy in the mitochondria (although mitochondrial energy supply may be poor as well), but rather an acute temporary shortage of ATP/ADP molecules with which convey the energy generated in the mitochondria to where it is needed in the cell. In other words, PEM is an acute problem of transport of energy, where you temporarily do not have enough ATP/ADP energy transportation molecules.
If you want an analogy: imagine that the mitochondria are like oil refineries making energy in the form of gasoline; and imagine that the ATP molecules are like gasoline trucks filled with gasoline and transporting this fuel to where it is needed, and that the ADP molecules are like empty gasoline trucks that have delivered their fuel, and are returning back to the refinery to be refilled again.
Myhill, Booth and McLaren-Howard are saying PEM arises when the body inadvertently temporarily loses many of its gasoline trucks, so it does not have enough trucks to distribute the fuel energy to where it is need. You only get over the PEM period when your body manufactures some brand new gasoline trucks to replace the lost ones (manufactures more ATP/ADP molecules), so that you can start efficiency delivering the fuel energy again.
So this is a compelling theory of how PEM may arise.
I was thinking that Myhill, Booth and McLaren-Howard's ATP/ADP molecule restocking theory of PEM suggests that D-ribose supplementation specifically during the PEM period might help mitigate PEM, since they point 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 Sarah 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, Booth and McLaren-Howard are saying that as a consequence of this shortage of ATP/ADP molecules (the gasoline trucks), the body desperately tries to manufacture new ATP molecules (manufacture more gasoline trucks) by any route it can. And one route of manufacturing ATP is 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.
So this would explain why ME/CFS patients generate far higher levels of lactic acid during physical exertion: it is just a 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 to clear lactic acid by converting it back to glucose, it 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 a bit of 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, Booth and McLaren-Howard 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, Booth and McLaren-Howard are theorizing that PEM may be due to an acute shortage of ATP/ADP molecules (due to these molecules being broken down and ultimately dumped out of the body in the urine), 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 metabolism processes whose efficiencies are measured by the "ATP Profiles" test, and which were found to be poorly functioning in ME/CFS.
These five energy metabolism processes 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 cell's 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.
In terms of the amount of ATP molecules present in the cells of ME/CFS patients, the Myhill 2009 study found ME/CFS patients only have around 60% of the ATP of healthy controls. Thus there is a major ATP energy shortage in the cells of ME/CFS patients.
(You can derive this 60% figure from Figure 2A of the study, where you see that on average, healthy controls have ATP concentrations of around 2 fmol per cell, whereas on average ME/CFS patients have around 1.2 fmol per cell, with some patients having as little as 0.9 fmol per cell.)
(2) ATP Ratio = the fraction of ATP in the cell that is complexed with magnesium
The majority of ATP molecules present in cells are bonded onto magnesium ions, to create a complex known as Mg-ATP. This bonding to magnesium is necessary in order for ATP to yield its energy; ATP molecules that are not bound to magnesium are not able to liberate the energy they carry. Thus an important factor in energy metabolism efficiency is the percentage of ATP in the cell that is bonded to magnesium, as only this percentage can supply energy. This percentage is given by the ATP Ratio. The ATP Ratio is also an indication of the amount of magnesium in the cell.
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 post and the 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, Booth and McLaren-Howard found that around half the ME/CFS patients in their studies had oxidative phosphorylation running normally (these they labelled Group A patients); but the other half of patients had their oxidative phosphorylation partially blocked and running at low efficiency (these they labelled Group B patients).
In ME/CFS patients whose oxidative phosphorylation is running normally (Group A), they found cellular metabolism uses increased anaerobic 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 adenylate kinase reaction is the same process which it is theorized leads to PEM, via the break down and loss of the energy-carrying ATP/ADP molecules. Ref: Myhill 2013.
D-ribose may be an especially important nutrient for Group B patients. 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.
(4) Translocator Protein Out = efficiency of ADP transport out from the cell
One job of translocator protein (ANT protein), which is located on the inner mitochondrial membrane, is to transport ADP in the cell across the inner mitochondrial membrane, and into the mitochondrion, for recycling back to ATP.
(5) Translocator Protein In = efficiency of ATP transport into the cell
The other job of translocator protein (ANT protein) is to transport the energy-carrying ATP molecules created in the mitochondria (from recycled ADP) across the inner mitochondrial membrane and into the cell, where their energy is used for cellular functioning. The efficiency of this ATP transport process across the mitochondrial membrane is another important factor in the efficiency mitochondrial energy production.
Dr Myhill says that translocator protein (ANT) 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 processes, 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: citrate, isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, oxaloacetate. Replenishing any one substrate will replenish all of them.
In Myhill 2012 they state:
Note that in the Myhill studies, when they refer to the "translocator protein", they actually mean the adenine nucleotide translocator (ANT), also called the ATP-ADP-translocator. ANT is a protein located on the inner mitochondrial membrane.
It is confusing that Myhill et al to refer to ANT as the "translocator protein", because the term "translocator protein" normally refers to a different protein called TSPO, which is located on the outer mitochondrial membrane. Both ANT and TSPO work in conjunction to ferry ATP out of the mitochondria; but they are two separate proteins.
Could Enterovirus-Triggered Autoantibodies Be Blocking The Mitochondrial Translocator Protein in ME/CFS?
I came across an interesting connection between coxsackievirus B, autoimmunity and the mitochondrial adenine nucleotide translocator (ANT): this study found autoantibodies which target and disable ANT in patients with viral myocarditis and dilated cardiomyopathy, 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 found in ME/CFS. The study authors said:
The authors are proposing a molecular mimicry-type autoimmunity, where antibodies that target the virus VP protein also unfortunately cross-reactive to ANT — thus in fighting the virus, the immune system antibodies inadvertently attack and block the crucial ANT protein on mitochondria.
It is known that energy metabolism in myocarditis and dilated cardiomyopathy is running at low efficiency, due to ANT dysfunction. The same autoimmune-mediated disruptions to ANT could thus also be happening in ME/CFS.
As long ago as 1985, ME/CFS researcher Prof Peter Behan stated in this paper that he thought something like may be the case in ME/CFS:
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.
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:
(i) the fact that ME/CFS is associated with infection from certain viruses, particularly coxsackievirus B
(ii) the fact that ME/CFS likely involves autoimmunity
(iii) the fact that energy metabolism appears to be dysfunctional in ME/CFS
A coxsackievirus B-triggered ANT autoantibody could explain all these features.
More detailed info on Prof Peter Behan's ANT protein autoantibody theory of ME/CFS is found in this thread.
Study Results: Defects in 5 Energy Metabolism Processes in ME/CFS
For the 71 ME/CFS patients in the Myhill 2009 study, figure 2 below shows how their five energy metabolism processes (labelled A to E) were operating 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 metabolism process 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 metabolism process efficiencies of the healthy controls.
This shows that these 5 energy metabolism processes in ME/CFS patients are generally operating at a reduced output compared to healthy people. Similar low energy metabolism process efficiencies were found in the 138 ME/CFS patients of the Myhill 2012 study.
The Five Energy Metabolism Process Efficiencies of ME/CFS Patients and Healthy Controls
Figure 2 from Myhill 2009
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 processes of energy metabolism. So in the study, the authors combined the efficiency figures for each of the five energy metabolism processes 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.
It is apparent from this graph that the Mitochondrial Energy Score roughly separates ME/CFS patients from healthy controls; and furthermore, as the MES roughly 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)
A summary of Myhill, Booth and McLaren-Howard's energy metabolism defect research can be found on Dr Sarah Myhill's website:
Video in which Dr Sarah Myhill explains the mitochondrial dysfunctions in ME/CFS, and (at timecode 20:53) details 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.
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