From the Journal of Neurology and Neurobiology, 10 September 2015. Full text available.
The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Family Physician/GPwSI, Soerabaja Research Center, The Netherlands
*Corresponding author: Mark Vink, MD, Family Physician/GPwSI, Soerabaja Research Center Amstel 38, 1096 HH Amsterdam, The Netherlands, E-mail: firstname.lastname@example.org
In this study the muscle bioenergetic function in response to exercise in severe ME was explored to see if the underlying metabolic problem in ME, responsible for the severe difficulties with trivial exercise, and the severe loss of muscle power, could be discovered.
Inorganic phosphate, creatine kinase and lactate were measured in a former Dutch National Field Hockey Champion, who is now a patient bedridden with severe ME, before and 5 minutes after very trivial “exercise”, from which his muscles needed 12 hours to recover.
Inorganic phosphate and creatine kinase were both normal, however, lactate after this trivial exercise was very high, and further testing showed that a second batch of lactic acid was excreted after the same exercise with a 6-fold delay, showing that the lactic acid excretion was impaired and split into two. And this was delayed up to 11- fold by eating closer to the exercise.
This study found that in severe ME, both the oxidative phosphorylation and the lactic acid excretion are impaired, and the combination of these two is responsible for the main characteristic of ME, the abnormally delayed muscle recovery after doing trivial things.
The muscle recovery is further delayed by immune changes, including intracellular immune dysfunctions, and by lengthened and accentuated oxidative stress, but also by exercise metabolites, which work on the sensitive receptors in the dorsal root ganglions, which in severe ME are chronically inflamed, and are therefore much more sensitive to these metabolites, which are produced in high quantities in response to trivial exercise, which for ME patients, due to the underlining metabolic problem, is strenuous exercise. And a similar problem is most likely responsible for the abnormally delayed brain recovery after doing trivial things.
This study also shows that the two metabolic problems are the result of an impaired oxygen uptake into the muscle cells or their mitochondria and in combination with the Norwegian Rituximab studies, which suggest that ME is an autoimmune disease, it is suggestive that antibodies are directly or indirectly blocking the oxygen uptake into the muscle cells or their mitochondria.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic multi-system disease that can lead to striking debilitation [1- 3]. The pathophysiology is related to activation of immunoinflammatory pathways and autoimmune responses underpinned by a state of energy depletion  and elderly patients with ME/CFS are at increased risk for non-Hodgkin’s lymphoma .
As reported by Jason et al. the median age of death for cancer in the United States is 72 versus an average age of 47.8 if the person also has ME/ CFS and the average age of death of heart failure is 83.1 versus 58.7 years if the person also has ME/CFS . What this means is that ME/CFS patients who died of cancer or heart failure were considerable younger than what would have been expected from the general population, which means that ME/CFS increases the risk of death from these conditions dramatically , which constitutes indirect proof that ME/CFS is a physical disease.
A quarter of ME/CFS patients have severe ME/CFS, are homebound or bedridden and suffer major functional impairments [2,7] to the point that some are tube fed due to dysphagia and /or dysparesis of the stomach caused by autonomic dysfunction which is a frequent finding in ME/CFS .
Patients with severe ME are bedridden because of a lack of muscle power, not because they are tired, yet hardly any research is done on patients with severe ME to find out why they are so severely disabled.
ME and CFS are often used interchangeably, even though the case criteria for ME and CFS define two distinct, partially overlapping diseases , which have different cytokine profiles .
The diagnosis ME requires both M and E problems, whereby M stands for Myalgic i.e. muscle pain and muscle energy production problems and E for Encephalomyelitis, i.e. specific neurological, neuroimmune and neurocognitive problems.
The main characteristic of ME is an abnormally delayed muscle recovery after doing trivial things , as witnessed and documented by infectious disease specialist Dr Melvin Ramsay after the 1955 outbreak of an unknown disease in the Royal Free Hospital in London  which at first was thought to be an atypical form of poliomyelitis  and later became known as ME. Dr Ramsay also documented that the diagnosis of ME should not be made in the absence of an abnormally delayed muscle recovery after doing trivial things .
This complaint of delayed muscle recovery from fatiguing exercise in ME/CFS was confirmed and objectified by Paul et al. who let patients and sedentary controls carry out a fatiguing exercise test with their quadriceps muscles and found a big difference in muscle recovery time .
These days the distinctive feature of ME is often referred to as “postexertional malaise” (PEM), and encompasses disabling and persistent muscle and/or brain fatigue following minimal exertion, usually accompanied by increases in symptoms in general, and muscle and/or brain symptoms in particular, including cognitive dysfunction [1,2,9]. VanNess et al. found that PEM in ME/CFS is incapacitating and that ME/ CFS patients responses to exercise are distinctively different from those of sedentary controls who are deconditioned because they do not like or want to do exercise contrary to ME/CFS patients who are very keen to exercise but are unable to because of an underlying metabolic problem .
Other common ME/CFS symptoms include, but are not limited to, sleep disturbance, pain, and symptoms associated with autonomic dysfunction such as orthostatic intolerance, postural orthostatic tachycardia syndrome (POTS), light and sound hypersensitivity, dizziness, tinnitus, severe headaches and/or gastrointestinal disturbances. Muscle and/or brain fatigue in ME are not alleviated by rest and may be exacerbated by physical or cognitive activity [1,2]. The more muscle and/or brain power you lose, the longer the recovery periods become. In my case if I walk the 5 to 6 yards to the toilet and back, it takes 12 hours before I have enough muscle power to walk the same trivial distance again.
A minimal increase in a ME patient’s typical level of activity, has a dramatic negative impact on the ability to carry out both physical and cognitive activities of daily living [1,2]. In other words if you go over your limit you get a relapse and the bigger the relapse the less likely you are to recover from it. Whereby the severity of the symptom flare after moderate exercise is linked to cytokine activity .
I developed ME after picking up pneumonia from a patient, who coughed me in the face, and during the first few weeks of falling ill with ME, my legs needed 15 minutes to recover from walking 20 to 30 yards, before I could walk the same trivial distance again, which illustrates the abnormally long periods of rest to recover from minimal exertion. In the days before I developed ME, walking that distance was easy, even though I was still recovering from pneumonia, coughing a lot and still on antibiotics. So suddenly, from one day to the next, I lost about 70- 80% of power in my legs, about 50-60% of power in my arms, I began to suffer from severe dizziness, I started to have daily headaches, from which I had never previously suffered, and I started to have problems sleeping for no reason, which I never had before either. The problems with walking were even stranger because I looked well, I didn’t feel ill and before the pneumonia I was fit and well, I was hardly ever sick and shortly before I fell ill with pneumonia, I was running 3-4 times a week, with a long run of 20 to 25 km on Sundays and I do not smoke and hardly ever drink alcohol.
Before acquiring the illness most patients were healthy, leading full active lifestyles and ME/CFS most frequently follows an acute pro-dromal infection, often a respiratory infection or an acute “flu-like” illness . And I’m a good example of both. I love sports and amongst things I am a former Dutch national field hockey champion, captain of my team.
The distinctive feature of CFS [9,15] on the other hand is chronic fatigue which must have lasted for 6 months or more, which is unexplained and needs to be accompanied by at least four out of eight symptoms, e.g. sore throat, unrefreshing sleep, and headaches. While post-exertional malaise is not obligatory for CFS [9,15], (chronic) fatigue is not mandatory for the diagnosis of ME [9,15].
Exercise intolerance is a cardinal feature in ME and various high quality studies found decreased physiological exercise capacity in individuals with ME/CFS [1,8,12-16] and using novel magnetic resonance techniques Jones et al. identified a distinctive, reproducible muscle bioenergetic abnormality in patients with ME/CFS , the degree of which not only associates with autonomic dysfunction, found in the majority of ME/CFS patients  but also with a characteristic cardiac bioenergetic impairment .
Various studies have observed impaired skeletal muscle metabolism in ME/CFS , acidosis during exercise, taking 4 times longer for the pH to go back to normal in ME/CFS [8, 16] and acidosis inhibits oxidative phosphorylation in contracting human skeletal muscle .
Wong et al. found low intracellular concentrations of ATP , confirming that the impaired physical activity in ME/CFS compared to healthy controls is related to a bioenergetic muscle abnormality which makes moderate and vigorous activity almost impossible and if it gets worse patients loose the muscle strength or power to sit, stand or walk and therefore they become bedbound with severe ME.
As noted by Morris et al. many studies have demonstrated a significant positive correlation between markers of inflammation and symptom severity . And a rapid decline of inflammation in patients corresponded with a decline in severity of fatigue and amelioration of their entire symptom profile . Markers of chronic inflammation have also been detected in skeletal muscle and correlate with objective measures of muscle fatigability .
Energy for skeletal muscle contraction is supplied by anaerobic and aerobic metabolic pathways. The aerobic system is the most efficient energy source, producing up to 18 times more energy in the form of ATP than if glucose was used anaerobically. But the downside of the aerobic system is that without oxygen it doesn’t function .
The glycolysis is the anaerobic metabolic pathway to produce ATP, used for bursts of all-out exercise lasting from 60 to about 90 seconds as reported by De Feo et al. , and is a very fast way to produce energy. During glycolysis, carbohydrate, in the form of either glucose or glycogen, the stored form of glucose, is broken down through a series of chemical reactions ultimately forming lactate. Very little energy is produced this way, but the trade-off is that you get the energy very quickly if oxygen demand outstrips oxygen supply [20,21].
The other problem of the anaerobic glycolysis is an increase in hydrogen ions and lactate, which causes muscle acidosis, and the production of metabolites in the form of ADP, Pi and potassium ions [21-23]. Acidosis and the accumulation of these metabolites cause a number of problems inside the muscles, including inhibition of specific enzymes involved in the anaerobic glycolysis and in muscle contraction leading to a very rapid loss of muscle power, i.e. within 1 to 2 minutes, with concomitant quickly increasing muscle pain [18,20-23] to the point that after 1 to 2 minutes of anaerobic exercising, one can hardly stand on one’s legs anymore. And this is exactly what happens if I walk the trivial distance of 5 to 6 yards to the toilet and back. And the longer I need to sit on the toilet, the longer it takes me to complete this trivial exercise, the more muscle power I lose and the more muscle pain I’ve got.
There has been substantial research to show that a build-up of acid within muscle or plasma is one of the factors which causes fatigue  and artificially induced acidosis can impair muscle contractility even in non-fatigued humans .
A number of papers have challenged this model to explain muscle fatigue. In place of acidosis it may be that inorganic phosphate is a major cause of muscle fatigue  which is produced during the breakdown of ATP to ADP. However, there are several limitations regarding this phosphate hypothesis, one of them is that loading of acid neutralizing agents, when ingested shortly before high intensity exercise, means one can go faster or further , which was one of the reasons why Robergs et al.  concluded that increased lactate concentration remains a good marker for the onset of fatigue.
The pain and symptoms in my legs after a trivial walk feel very similar, albeit a lot worse, to the muscle symptoms I had in the past after a very strenuous training, and the objective therefore was to try and identify the underlying bioenergetic muscle problem in ME, responsible for the exercise intolerance, rapid muscle fatigue and delayed muscle recovery.
The study by Byrne et al.  showed that skeletal muscle carnitine, phosphorylase, all glycolytic enzymes and the mitochondrial marker enzymes monoamine oxidase, isocitrate dehydrogenase and cytochrome oxidase were normal. They therefore concluded that there was no major intrinsic defect in the muscle energy pathways in ME/CFS .
Edwards not only noted that muscle fatigue and pain occurring at rest without any exercise, suggests it is psychological in origin but also that if it happens or gets worse after exercise, as is the case in ME, it’s indicative of a muscular problem . Exercise fatigue or pain should ideally be reproduced by an appropriate provoking exercise test and plasma creatine kinase and lactate are specific indicators of a muscular cause .
I hypothesized that I might be able to come up with the bioenergetic reason for my muscle problems by measuring my inorganic phosphate, creatine kinase and lactate before and after exercise, as it’s clear from the literature and my symptoms, that there is a major bioenergetic problem responsible for my severe loss of muscle power and the very long muscle recovery times after trivial walks.
Successfully identifying the underlying metabolic problem in ME/ CFS would make it easier for doctors to diagnose the disease and prevent symptom exacerbation or relapses from exercise regimes of which patients have been complaining for a long time and which was objectified by a graded exercise trial by Black et al.  but also by a recent large survey by the British ME Association which concluded and asked for the immediate withdrawal of harmful Graded Exercise Therapy (GET) as a treatment for ME/CFS .
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