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Reproduced with generous permission from the April 2008 issue of Dr. Bell’s e-newsletter, Lyndonville News.

ME/CFS is a disorder involving the cells’ energy-producing mitochondria – but it’s a mitochondrial disease like no other, Dr. Bell believes. He explains why it hasn’t been diagnosed, classified, and studied like other kinds of mitochondrial diseases - and why a change may be “just around the corner.”

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In the past week I have seen two patients who had an exercise lactate test which showed an elevation of blood lactate after mild exercise [considered a sign of mitochondrial damage]. They were told by their physician that they had “mitochondrial disease.” They were advised to take some vitamins, maybe some CoQ-10, and have a nice day. Like nearly everything else, the term mitochondrial disease left these patients feeling bewildered and somewhat lost.

While I agree that ME/CFS is a mitochondrial disease, this term needs clarification because ME/CFS is a mitochondrial disease like no other.

Until recently, when a child was diagnosed as having a mitochondrial disease, it was a disaster, even a death sentence, for it meant that there were major abnormalities in the mitochondrial or nuclear DNA that regulated energy production. Without energy (ATP) it is impossible to survive. These diseases are called MELAS, Kearns-Sayre, Leber hereditary optic neuropathy, and so on. Nearly three hundred mitochondrial illnesses have been identified from genetic mutations. It is a specialized area of pediatrics, where it is possible to measure severe abnormalities in the mitochondria on muscle biopsy testing.

This is what most clinicians think of when the words "mitochondrial disease" are mentioned, but these illnesses do not, in general, apply to ME/CFS. Many patients with ME/CFS have had muscle biopsies, and most of the mitochondrial tests on these biopsies are relatively normal. We will return to why this is in a bit.

What are Mitochondria?

Think of mitochondria as the power factories of the cell.

Nearly every cell in the body has them, usually around 500 or so in every cell.

They take in oxygen and glucose (blood sugar) and put out carbon dioxide and energy (ATP).

There are two hundred different steps in this process, and we will quiz you after this article. Actually, all you need to know is that:

ATP is the prime energy storage chemical (battery) of the body, and

Oxidative phosphorylation (ox-phos) is the complex of electron transport chains that do the major work of conversion.

Because the mechanism of energy production is essential to nearly every cell, a defect will have symptoms in every organ system. Sound familiar? Oxidative metabolism, the ability to utilize oxygen to produce energy, is quite efficient, and it is fascinating to look at the theories of how it came to be part of our cells.

However, when the energy demand is excessive, the cells revert to a more primitive, and less efficient, form of energy production - anaerobic metabolism (metabolism without oxygen). For an interesting study on the anaerobic threshold [point of reversion] in ME/CFS, see the literature review that follows.

When to Suspect Mitochondrial Disease

In a recent review article (Haas et al., 2007) there is a list of symptoms that suggest looking for mitochondrial disease. Among these symptoms are neurologic symptoms such as ataxia (coordination problems), myoclonus (twitching), and encephalopathy (brain injury), exercise intolerance, sensitivity to general anesthesia, and constipation.

A score sheet has been developed to help in when to suspect mitochondrial disease - and most ME/CFS patients would fall into the positive range. For lots of information on mitochondria please go to http://www.mitosoc.org. But remember that they are talking about “conventional” mitochondrial disorders, not ME/CFS.

A Mitochondrial Problem Can Be
Secondary to Some Other Problem

There is another form of mitochondrial disease, or “secondary mitochondrial disease.” In secondary mitochondrial disease the primary problem is not with the mitochondria, but some other problem that messes up mitochondrial function. There are many illnesses where the primary defect ends up causing problems with the generation of energy in mitochondria.

For example, thyroid hormone is needed for successful oxidative phosphorylation. With hypothyroidism (low thyroid) energy production is impaired, and fatigue, weakness, temperature regulatory problems, and difficulty concentrating result. This is one of the reasons that when you start to describe fatigue to your primary care physician, he or she begins to write out a script to test for thyroid hormone.

So What Is the Problem?

Why has ME/CFS not been diagnosed, studied and classified like other mitochondrial diseases? There are several reasons:

a. Mitochondrial disease is thought of by clinicians as a fatal disease of infancy, not one that occurs later in life.

b. Mitochondrial disease is usually thought of as a fixed, structural disease, and ME/CFS is a relapsing, remitting illness with some persons even becoming entirely well.

c. Mitochondrial diseases are hard to diagnose, requiring muscle biopsies and detailed ox-phos testing.

d. Ox-phos testing is often normal in ME/CFS, and this has been the critical piece that has diverted attention from mitochondria.

e. Physicians are used to thinking of organ-specific diseases (liver, kidney, etc), and mitochondria are in all cells.

f. Few physicians have taken ME/CFS seriously until recently, and research in this area has been scant.

Of the above reasons, only reason “d” is important to us here (ox-phos testing is often normal in ME/CFS). In 1990 I did a muscle biopsy study on 10 ME/CFS patients with Dr. June Aprille, PhD, an expert in cellular metabolism. All ten persons had relatively normal ox-phos studies. Although we did not publish this finding, it is consistent with the few published studies that have been done.

How can you have mitochondrial disease when the mechanism tests normal? I think that the answer to this paradox is just around the corner.

Hypothesis

If you have a patient with emphysema who is sitting in an armchair, he or she is not out of breath. You can measure the damage in tests, but to make symptoms, you have to “stress” the system – make the patient run up and down stairs. If a person with G-6-PD deficiency [linked to fava bean allergy] is sitting quietly, the blood looks normal. But feed this person fava beans and abnormalities quickly become obvious.

Persons with ME/CFS keep themselves at a balance point. They rest for two hours, then do a half hour of activity, then rest, then do more and so on. The worse the illness, the less overall activity is possible. If a ME/CFS patient does absolutely nothing for a few days, they usually feel pretty good. But go to the shopping mall for eight hours and the crash occurs.

Here is the problem: In the patients studied for mitochondrial disease, they have been resting up (staying above the balance point), and a muscle biopsy done at that moment will probably not show much. But have a ME/CFS patient exercise, and then study mitochondrial function. My hunch is that the ox-phos reactions will be seriously impaired, but this has not been systematically and methodically done. For me, this hypothesis is generated by the VanNess, Snell, and Stevens “Two-day Exercise Test” study described in the next section.

There are lots of studies that implicate mitochondrial problems; Dr. Hirohiko Kuratsune and carnitine; Dr. Suzanne Vernon and genomics; Dr. Kenny DeMeirleir, Dr. Martin Pall, Dr. Paul Cheney, and many others. But this problem cannot be studied in tiny fragments. It is time for a good study to look at the different steps of the body’s ability to generate energy. Let’s hope we get to see it within our lifetimes.

Literature Review - the “Two-day Exercise Test”

In the most recent Journal of Chronic Fatigue Syndrome (Vol 14, Number 2, 2007) there are two articles which may be the first to offer an objective proof of disability in ME/CFS. More importantly, if shown to be correct, they may give us an avenue to test and measure the biochemical abnormality which causes the symptom pattern. I would like to briefly review these two papers and present a case of pediatric ME/CFS which demonstrates the same abnormalities.

In the first of these papers, Margaret Ciccolella, a lawyer, teams up with Staci Stevens, Chris Snell, and Mark Van Ness of the University of the Pacific to review the legal issues surrounding exercise testing and disability(1). As everyone familiar with ME/CFS well knows, insurance companies require proof of disability, which a standard exercise test may or may not demonstrate. However, even if disability is present, insurance companies have been quick to say that the patient was not trying hard enough, or that the patient is de-conditioned.

The second paper of this series by VanNess, Snell and Stevens explains the two-day exercise test and presents results for six patients with ME/CFS(2).

As clinicians have observed, the symptom of “post-exertional malaise” is one of the most distinguishing features of CFS. This symptom is listed as one of the eight in the criteria of the Centers for Disease Control(3), and is central to the diagnosis in the recent Canadian Case Definition(4) and the proposed pediatric case definition(5). It is beginning to look like the symptom of post-exertional malaise is at the root of disability, and may be central to the pathophysiology of this complex illness spectrum.

A person with ME/CFS may be at home for several days doing little except basic activities of daily living. When this patient decides to go shopping, he or she will drive to the mall and shop for one or two hours. During this time, observers would say that the person looks entirely well, not appearing disabled. However, following this activity the patient will experience an exacerbation of pain and other symptoms of ME/CFS. This exacerbation may last one, two or three days, and, in my opinion, the more severe the illness, the longer and more severe the exacerbation.

This phenomenon is known as post-exertional malaise. The symptoms of the illness (malaise) are exacerbated by mental, physical or emotional activities (post-exertional). In an employment environment, the patient may be able to do a job well for one or even several days. However, disability lies in the inability to sustain this normal level of activity. The two-day exercise test is the first to begin to explain this phenomenon.

The exercise test is no different from what has been used for years. The patient exercises on a stationary bicycle (bicycle ergometry) and breathes through plastic tubing to measure the concentration of oxygen and carbon dioxide as well as the total amount of air. The six female patients and six sedentary matched control subjects of the study were all able to achieve maximal exertion. The ME/CFS patients had a slightly lower V02max (maximal oxygen utilization) than controls (28.4 ml/kg/min vs. 26.2 ml/kg/min) and lower VO2 at anaerobic threshold (15.01 ml/kg/min vs. 17.55 mg/kg/min) on the first day of exercise testing.

These values are not dramatic, nor are they statistically significant.

It is on the second day that interesting results are seen. The same test was repeated the following day for all 12 subjects. As is often the case, sedentary controls improved slightly in their ability to utilize oxygen, going from 28.4 to 28.9 ml/kg/min for VO2max and from 17.55 to 18.00 ml/kg/min for oxygen utilization at anaerobic threshold. The CFS patients however worsened in both categories: VO2max fell 22% from 26.23 to 20.47 ml/kg/min, and oxygen utilization at anaerobic threshold fell 27%, from 15.01 to 11.01 ml/kg/min.

To put this into perspective, these values are in the “severe disability” range on the AMA guidelines, and the decline in function from day one to day two cannot be explained by inactivity.

Sedentary or de-conditioned persons do not change their oxygen utilization because of an exercise test. Even patients with heart disease, cystic fibrosis or other diseases do not vary more than 7% from one day to the next. However, the patients with ME/CFS in this study had a significant drop; something occurred because of the test on the first day that interfered with their ability to utilize oxygen on the next day. And this is exactly what patients with ME/CFS have been describing with the symptom of post-exertional malaise.

As the authors state, “The fall in oxygen consumption among the CFS patients on the second test appears to suggest metabolic dysfunction rather than a sedentary lifestyle as the cause of diminished exercise capacity in CFS.”

Conclusions

The results of the two-day exercise testing are objective and not dependent upon subjective symptoms. Moreover, hypochondriasis, intentional falsification, and/or poor effort can be detected by the physiologic parameters. Therefore:

The two-day exercise test, if confirmed in a larger trial, could become a clinical trial end point.

More importantly, evaluations could be designed which would demonstrate the specific metabolic abnormality generated by the exercise of day one and demonstrated on the second day exercise test.

It would be my hope that these findings be explored without delay.

Sources:

Ciccolella M, Stevens S, Snell C, VanNess J: "Legal and Scientific Considerations of the Exercise Stress Test". JCFS 2008, 14(2):61-75.

VanNess JM, Snell CR, Stevens S: "Diminished Cardiopulmonary Capacity During Post-Exertional Malaise". JCFS 2008, 14(2):77-85.

Fukuda K, Straus S, Hickie I, Sharpe M, Dobbins J, Komaroff A, Group ICS: "The chronic fatigue syndrome: a comprehensive approach to its definition and study." Ann Intern Med 1994, 121:953-959.

Carruthers B, Jain A, DeMeirlier K, Peterson D, Klimas N, Lerner A, Bested A, Flor-Henry P, Joshi P, Powles ACP et al: "Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols." J Chronic Fatigue Syndrome 2003, 11(1):1-12.

Jason L, Bell D, Rowe K, Van Hoof E, Jordan K, Lapp C, A G, Miike T, Torres-Harding S, DeMeirleir K. "A Pediatric Case Definition for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome." J CFS 2006, 13:1-44

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Dr. Bell's Disclaimer: Any medical advice that is presented in the Lyndonville News is generic and for general informational purposes only. ME/CFS/FM is an extremely complex illness and specific advice may not be appropriate for an individual with this illness. Therefore, should you be interested or wish to pursue any of the ideas presented here, please discuss them with your personal physician.

Note: This information has not been evaluated by the FDA. It is not meant to prevent, diagnose, treat or cure any illness, condition or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.

 

 

Important Cofactors and Coenzymes in Mitochondrial Function:

There are therefore a number of goals when in comes to assisting a return to normal mitochondrial function in the body, with a positive knock on effect on many other systems of the body. As mentioned above, these are increasing the efficiency of ATP conversion and distribution (i.e. actual energy release), speeding up the rate of recycling of ADP back to ATP again (i.e. energy recovery times and energy reserve), and also providing the body with enough raw materials to produce new ATP (i.e. replenishing depleted energy reserves - having converted some of the ADP to non-recoverable AMP in lieu of any ATP being available).

A large number of different metabolites and co-factors are used by the body in the Krebs (citric acid) cycle, a series of chemical reactions that enable glucose to be used for energy production within the cells of the body. Some of these are discussed below.

Krebs Cycle Organic Acids

 

Citric acid

(Isocitric acid)

Alpha-Ketoglutaric acid (AKG) - the conversion from AKG to Succinic acid involves the reconversion of ADP to ATP

Succinic acid

Fumaric acid - oxidised form of Succinic acid

Malic acid

(Oxaloacetic acid)

Pyruvate - precursor to Acetyl Coenzyme A, which combines with Oxaloacetic acid (above) to form Citric acid

Those organic acids that are not significant supplementally are shown above in brackets. There are a number of possible organic acids that may not be converting properly in the Krebs Cycle, as can be seen above.

High levels of Citric acid and Malic acid are available in fruits (e.g. apples - rich in both) and fermented foods (e.g. Kombucha - rich in Malic acid). Malic acid supplements are available in acid form (i.e. Malic acid) or salt form (e.g. Magnesium Malate); and in combination products such as Ultra Muscleze. Malic acid is frequently shown to be low in CFS sufferers (together with Magnesium).

Alpha-Ketoglutarate (AK) is the salt form of the acid Alpha-Ketoglutaric Acid (AKG). KA supplements are often found in the form of Potassium Magnesium Alpha-Ketaglutarate (K-Mag KG).

Another is Pyruvic acid which is produced from carbohydrates and is a precursor to Co-Enzyme A. Typically however, malic acid is most commonly deficient of all these acids.

Magnesium - is particularly important in regulating and stabilising ATP, and is often displaced by the presence of heavy metals. With a deficiency of Magnesium, the ATP becomes over-regulated or inhibited, resulting in low energy levels. Magnesium helps to fire up various essential enzymatic reactions. Nutritional elements such as Magnesium, Zinc and Selenium have an important role in protecting the body from the effects of heavy metals, and those individuals with elevated heavy metal levels have a greater requirement for these nutrients (and a corresponding great need to detoxify the heavy metals from their bodies). Magnesium is best taken in Chelated form, e.g. Citrate or Glycinate, together with the amino acid Taurine to help carry it into the cells.

 

Active B1 - Thiamine PyroPhosphate (TPP), a.k.a. Thiamine Diphosphate (TDP) or Cocarboxylase, is the biologically active form of Vitamin B1, Thiamine, and is used in the efficient burning carbohyrate and removing excess lactic acid (a cause of muscle ache).

 

Active B2 - Riboflavin, Vitamin B2, is also involved in the Krebs Cycle, as a cofactor in Complex I and II. There are two active, coenzyme forms of B2, Flavin Mononucleotide (FMN) and Flavin Dinucleotide (FAD). FMN is the coenzyme form of B2 found in supplement form.

 

Active B3 - A variant of Vitamin B3 (Niacin), known as Nicotinamide Adenine Dinucleotide plus high-energy Hydrogen, or NADH for short, is also involved in the Krebs cycle. Niacin can be obtained from protein but it is dependent on efficient protein digestion and amino acid conversion in the body. NADH and NAD are an essential part of the ATP to ADP conversion. Active B3 probably has most immediate noticeable effect on energy levels, but all B-vitamins are important to some degree in energy production. B3 levels can drop significantly if there is Peroxynitrite-related oxidative damage occurring in the body (to poly (ADP-ribose) polymerase enzyme DNA), having a knock on effect on the mitochondrial electron transport chain. Please see the Peroxynitrite page for more information.

 

Vitamin B5 - Pantethene (a biologicaly active form of Vitamin B5) is involved in the synthesis of Coenzyme-A (CoA). CoA is important in energy metabolism for pyruvate to enter the tricarboxylic acid cycle(TCA cycle) as acetyl-CoA, and for alpha-ketoglutarate to be transformed to succinyl-CoA in the cycle.

 

Active B6 - Pyridoxal-5-Phosphate the active form of Vitamin B6 can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis. P-5-P is also a required coenzyme of the glycogen phosphorylase enzyme, that allows glycogenolysis to occur.

 

Active B12 - The enyzme Methylmalonyl Coenzyme A mutase (MUT) requires vitamin B12 in the form Adenosylcobalamin (AdoB12). MUT is involved in carbohydrate metabolism, converting Methylmalonyl-CoA (MMI-CoA), the coenzyme A link form of methylmalonic acid (MMA), into Succinic-CoA (Su-CoA), the conenzyme A link form of succinic acid. It forms part of the Krebs cycle for the production of energy.

 

Acetyl-L-Carnitine (ALC or ALCAR) - is an amino acid that and allows proper transport and burning of excess fat and prevents mitochondria from shutting down. It is the acetylated ester of the amino acid L-Carnitine. Carnitine helps to transport ATP and ADP across the mitochondrial membranes, and to transport activated ATP to where it is actually used. It is manufactured intracellularly in the body from the Essential Amino Acids L-lysine and L-methionine, by a process of methylation i.e. does not float around in the blood stream (and thus urine) - and hence is usually not included as a parameter in amino acid analyses.

However the quantities manufactured endogenously are relatively low, especially if there is a bottleneck in the production of carnitine (i.e. impaired methylation, insufficient quantities or precursor(s), impaired enzymatic function, lack of availability of ATP for these enzymes, low levels of coenzymatic cofactors , etc.) Otherwise the body relies on external dietary sources of carnitine to maintain sufficient levels. External sources are limited to meat, i.e. other animal's cells. Vegetarians or vegans who do not supplement carnitine will not be ingesting any carnitine and will be relying solely on endogenously produced carnitine to enable them to fulfill their energy requirements. Dietary (meat) sources of L-Carnitine may also not cross the blood brain barrier efficiently in some individuals, or digestion and absorption may be impaired in those with digestive difficulties. A lack of carnitine, for any of the above reasons, may adversely affect the body's ability to produce energy on demand. In such cases, supplementation with Acetyl-L-Carnitine (and eating red meat if possible) will help.

A powerful antioxidant and a mitochondrial cofactor (transporter of ATP). It helps to lower the mitochondrial phase transition (which leads to apoptotic cell death), thus playing a protective role in mitochondria. It also helps to transport fatty acids into the mitochondria. The inner mitochondrial membranes' cardiolipin are made up predominantly of fatty acids. (90+% Omega 6 fatty acids).

www.renegadeneurologist.com/?s=acetyl-l-carnitine

http://en.wikipedia.org/wiki/Carnitine

http://en.wikipedia.org/wiki/Acetyl-l-Carnitine

The properties of Carnitine in its different forms is vastly different, and only one type may be absorbable by an individual at any given time. L-Carnitine is notoriously difficult to cross the blood-brain barrier. The body may only be able to utilise one form of Carnitine most effectively at a given time, and throwing the wrong kinds at it or too many different kinds may not necessarily increase the efficiency or absorption, ability to cross the blood-brain barrier or utilisation.

Acetyl-L-Carnitine is the form most widely recognised as being most appropriate and efficient. The Acetyl group allows it to more easily cross the blood-brain barrier, and the Acetyl group is broken off to be used to create Acetylcholine (the essential neurotransmitter), leaving the L-Carnitine to be utilised by the brain's cells. ALC also enahnces the release of dopamine from neurons and helps it bind to dopamine receptor sites. Acetyl-L-Carnitine has been noted to increase levels of neurite production (i.e. projections from the cell body of neurons) in the brain. For this reason, it is best to avoid taking ALC supplements in the evening, as it may interfere with one's ability to sleep. ALC is also a poweful antioxidant.

Besides Acetyl-L-Carnitine described above, Carnitine is also found in alternative forms, such as:

- L-Carnitine Fumarate - a blend of L-Carnitine and Fumaric acid, a Krebs cycle organic acid. The Biosint licensed forms are known as CarniShield and DuraCarn which are reputed to be highly bioavailable. It is used by a number of supplement manufacturers.

- Acetyl L-Carnitine Arginate diHCl (ALCA) - this is Acetyl-L-Carnitine blended with the amino acid Arginine. This is reputed to be four times more effective in stimulating neurite production in the brain than Acetyl-L-Carnitine.

- Acetyl L-Carnitine Taurinate HCl (a blend of Acetyl-L-Carnitine, Taurine and HCl).

- Glycine Propionyl L-Carnitine (GPLC).

Jarrow Formulas' CarnitAll 600 contains all of the above 4 forms. Jarrow states that the first three forms of Carnitine are for Cardiovascular function, whereas the GPLC is claimed to be a 'muscle-specific form of Carnitine that enhances endothelial function and promotes maximum muscular energetics'.

Life Extension's product 'Optimized Carnitine with GlycoCarn' contains Acetyl-L-Carnitine HCl and Acetyl-L-Carnitine Arginate Di-HCl (trademark - ArginoCarn), and a patented form of GPLC called Glycine Propionyl L-Carnitine HCl, known as GlycoCarn. The product does not contain any L-Carnitine Fumarate however. GlycoCarn is also available (without the other forms of Carnitine) in the Life Extensions product Peak ATP, discussed below.

I was muscle tested for different forms of Carnitine in April and June 2009, and neither GlycoCarn (GPLC HCl) nor L-Carnitine Fumarate were not wanted by the body, whereas (Jarrow Formulas) Acetyl-L-Carnitine was.


http://en.wikipedia.org/wiki/Carnitine

L-Lysine - is the precursor to L-Carnitine, and is the amino acid found in all proteins and enzymes in the body. Lysine is metabolised to make Coenzyme A, a necessary fuel of the Krebs cycle for carbohydrate metabolism and energy production. Lysine is also used to make Collagen, the connective tissue in humans and other mammals. A deficiency in Lysine will have a serious impact on enzyme and protein production, as well as energy levels, and often results in weight loss. Determine whether you are actually deficient in Lysine as supplementing Lysine may well boost your Carnitine levels intracellularly more effectively than supplementing Carnitine as above.

 

Lipoic Acid - is a cofactor in energy production, helping to regulate glucose metabolism. Lipoic Acid is active in all the tissues of the body and in its cellular compartments. Lipoic acid recycles both water and fat soluble antioxidant vitamins (e.g. vitamins C and E) and Coenzyme Q10, reducing them back to their non-oxidised original forms. Lipoic acid also improves sugar metabolism and energy production. It is a cofactor in the multienzyme complex that catalyzes the last stage of the process called glycolysis. Glycolysis is the first step in converting blood sugar (glucose), which is obtained from carbohydrates and proteins, into energy in a form that the body can use. This involves Magnesium, Active Vitamin B1 (TPP or TDP) and also Biotin, and so Lipoic Acid is best taken in conjunction with these other three supplements. Lipoic acid promotes the incorporation of cysteine into glutathione and combines synergistically with other antioxidants for greatly increased benefits. It is therefore frequently referred to as the ideal or universal antioxidant and free radical scavenger. It is also an excellent chelation agent. Please see the Detox page for more information.

 

Coenzyme Q10 - and also Copper, Sulphur and Iron - are vital parts of the Electron Transport System (ETS) that harvest ATP energy from our daily food intake. Q10 helps to transport electrons from one molecule to another, hence allowing for energy production and transfer to take place. Beta blockers, tricyclic antidepressants and phenothiazines actually block CoQ10 production in the body and way worsen the situation. Coenzyme Q10 is naturally produced by the body by a process of methylation. If methylation is impaired in an individual, then Q10 levels may be quite low. Coenzyme Q10, aka Ubiquinone, is the most common form of supplemental Q10. For the non-vegetarians, heart is the most concentrated naturally occurring nutritional source of Q10. Coenzyme Q10 is defined on Wikepedia at the following link.


http://en.wikipedia.org/wiki/Coenzyme_Q10

CoQmax CF is a trademarked product by XYMOGEN. It is a proprietary, patent-pending, crystal-free form of CoQ10 that is reputed to offer very high levels of absorption and bioavailability. It utilises a proprietary monoglyceride carrier. Each capsule contains 50mg of CoQ10 (as ubiquinone). Clinical trials have shown it to be over 8 times more absorbable than powdered CoQ10 and more than twice as bioavailable as other oil-based or 'nano'-dispersed formulas. An example dosage in extreme cases might be 2 capsules, twice a day or more.

Another readily absorbable form of Ubiquinone (Q10) is Jarrow Formulas' Q-absorb Co-Q10. This uses a form of Q10 called Kaneka Q10 which is under licence from the Kaneka Corporation of Japan, and uses the 'ProSome' Formula. It comes in 100mg capsules. It is reputed to be absorbed 3-4 times better than ordinary chewable Co-Q10 tablets. The best elevation of blood plasma Q10 levels with this product have resulted in exercise being performed at the time of taking it, according to studies. Jarrow also offer other Ubiquinone products, such as Q-absorb Co-Q10 Plus and Q-absorb Co-Q10 Ultra. Both of these products contain the Citrus extract Limolene, which is reputed to help prevent crystallisation of Co-Q10 and thus aid absorption. The 'Plus' version contains 300mg of Limolene per capsule, in addition to 600mg Lecithin. Jarrow claims Q-Absorb Ultra has been clinically demonstrated in humans to raise plasma Co-Q10 levels by 500% (a six-fold increase over baseline Co-Q10 levels). Whether Limolene is used in CoQMax CF by Xymogen above is uncertain at this point in time. Limolene, it should be noted, is also an antimicrobial oil used to kill intestinal parasites (protozoa or nematodes).

Ubiquinol is a bio-activated (un-oxidised), trans-isomer form of Co-Enzyme Q10 (ubiquinone) and is reputed to be much more readily absorbed or utilised, in studies up to twice as effectively. It can be found in a number of Ubiquinol supplements and also in Premier Research Labs 'CoQ10-Quinol' product or Healthy Origins Ubiquinol. It is manufactured under license from the Kaneka Corporation in Japan, under the trademark 'Kaneka QH'.

In April and June 2009, I was muscle tested for various forms of CoQ10 (Ubiquinone), also including a Ubiquinol supplement, and CoQmax was the only brand/form of CoQ10 that was found to be agreeable to his body (at those times).

An alternative to Coenzyme Q10 is Idebenone. It is a synthetic alternative to Coenzyme Q10, an organic acid. It is reputed to have many of the same chemical properties to Coenzyme Q10. From my understanding, it is really an 'optional' supplement, to be taken in addition to Coenzyme Q10 rather than instead of it, or not at all. According to Dr Ward Dean MD, Idebenone does offer some unique benefits over CoQ10, including superior ability electron transport. In low cellular oxygen environments, Idebenone is more efficient at preventing free radical damage than CoQ10, whilst helping cells maintain relatively normal ATP levels (particularly useful to tissues that are rapidly damaged by insufficient tissue oxygenation such as the brain and the cardiac muscle - although are we talking about states where the patient is not breathing here? Rather than CFS?).

http://en.wikipedia.org/wiki/Idebenone

Creatine - Creatine is a nitrogenous organic acid that helps to provide cells with energy until the Krebs cycle can start to produce energy. PhosphoCreatine is converted into ATP. It fills in the gap energetically between the 0.8s of energy (ATP) that cells have stored at any one time, and the 1.4 seconds it takes for the Krebs Cycle in the mitochondria to start producing more energy.

http://en.wikipedia.org/wiki/Creatine

By converting PhosphoCreatine into ATP during the initial stages of exercise, the body is able to provide energy before the body starts burn food to generate ATP. This can help to reduce the amount of ATP that is used up initially before more can be generated. Creatine helps to reduce lactic acid build up in the muscles and helps mitochondria to function efficiently at the start of a work out, and may also help with brain functioning.

Unlike the Krebs Cycle nutrients, Creatine is not stored in the mitochondria, but is found locally in the cell. 95% of the body's Creatine is found in the skeletal muscles.

Half of the Creatine in the body is derived from dietary sources, the other half is produced internally. Creatine is found in meat and fish, and vegetarians and vegans tend to have lower levels of Creatine unless they supplement it. Creatine tends to be denatured with heat in cooking. Creatine is manufactured by the body by a process of methylation, from the amino acids Arginine, Glycine and Methionine. However, if methylation is impaired, which it frequently is in patients with CFS and related conditions, and dietary sources are insufficient, then levels may be quite low. Those who are low in Creatine may benefit from taking Creatine Monohydrate or Creatine Ethyl Ester prior to a work out, or first thing in the morning. Bodybuilders are known to take creatine during high intensity weigh training workouts in order to perform addition reps at their maximum weight in order to build the maximum muscle mass in a session, and also to provide additional energy for intensive cardiovascular exercise (e.g. treadmills or jogging). Creatine is osmotically active and excessive supplementation, and in weight training applications, will result in increased water retention, especially in the muscles. This may result in a bloated or larger, ripped appearance, and may add as much as 1-2kg to one's normal weight. It has also been observed that regular creatine intake may encourage the liver to produce less creatine naturally, and so if supplemental creatine is then stopped, then the person may feel tired for a number of weeks before enzymatic creatine synthesis returns to normal to redress the balance. There are no known harmful effects from taking creatine, despite fears to the contrary. Creatine supplementation (and dosage recommendations) however should probably be based on ascertaining one's natural creatine levels and whether they require supplementation or not; and indeed whether the body reacts well to it using muscle testing, or other means, like any other form of supplementation.


www.pponline.co.uk/encyc/0164.htm

N-Acetyl Cysteine (NAC) - is a powerful antioxidant and useful glutathione precursor, as has been discussed on the Nutritional page and Inefficiency Liver Function and Detox pages. It also promotes oxidative phosphorylation, key elements of the respiratory chain, mitochondrial membrane integrity and mitochondrial homeostasis, thereboy delaying apoptosis (Programmed Cell Death). L-Cysteine may also be supplemented instead, however the Acetyl group may make it more absorbable in the brain. Supplementing directly with Glutathione is also an alternative option. In addition, Superoxide Dismutase (SOD) enzyme production is probably even more important that Glutathione in terms of ability to assist in respiration, protecting against superoxide damage.

 

Guanosine Triphosphate (GTP) - is a purine nucleotide is produced by a Krebs cycle enzyme in the process of producing ATP. It consists of a Guanosine molecule attached to a Ribose ring. Increasing one's purine intake (within limits as one does not want Gout) may assist increasing ATP levels.

 

Copper, Zinc, Manganese and Iron - SOD enzymes are bound to a metal element, copper, zinc, manganese or iron, and therefore it is shrewd to maintain adequate levels of these mineral elements in one's diet or supplement regime (as mentioned above), and to ensure one's levels do not drop below normal (according to relevant test results).

 

Chromium (III) - is a trace element that enhances the action of insulin (involved with carbohydrate, fat and protein metabolism). Chromium is a trace element and only small amounts are required. It should only be supplemented if levels are low, as excessive supplementation may lead to detrimental effects.


http://ods.od.nih.gov/factsheets/chromium.asp

Vanadium - is believed to be involved with glucose metabolism (enhancing , Na/K transport, adrenal catecholamine metabolism (oxidation), and inhibiting cholesterol synthesis (lowering total and LDL (bad) cholesterol levels). Vanadium is a trace element and only small amounts are required. It should only be supplemented if levels are low, as excessive supplementation may lead to detrimental effects such as decreased energy production.


www.umm.edu/altmed/articles/vanadium-000330.htm

Some of these cofactors are summarised and discussed in the article below by Ward Dean MD, entitled 'Restoring Mitochondrial Function and Bio-Energetics'. The mitochondria inner/outer membrane diagram above is also found here.

http://www.vrp.com/articleprinter.aspx?a=912

As one can see, there are a large number of bio-chemical compounds involved in energy production in the body. There are many more that have not been discussed here, including various organic acids and hormones. Any number of these may be deficient in the body in a sufferer of CFS or related conditions, and are required in the correct quantities and correct relative ratios for optimum metabolic function. Knowing exactly what is required and in what quantity is critical, and it is recommended to consult with your naturopath to address this area, rather than simply take every expensive supplement that is all the rage on the internet, as this approach is unlikely to be completely effective. For example, you are unlikely to notice any benefit in taking high doses of Ubiquinol (CoQ10) if your levels of CoQ10 are actually satisfactory. The main effect will the antioxidant effect - and there are cheaper and more effective antioxidants - but mainly the effect on your wallet. Identifying what is actually in dire need by the body is therefore of paramount importance. It is tempting to simply take a long list of the above supplements expecting them to work, but one must consider what cofactors, minerals, vitamins and amino acids are actually deficient, and tackle those, rather than the arbitrary list above. Indeed, the actual problem may not be what you expect and may well be less obvious, relating to other krebs metabolites, dysbiosis, other amino acids being deficient, low hormone and neurotransmitter levels, amongst other things. A 'holistic' approach is therefore required to get to the bottom of why mitochondrial function is poor.

There are a number of combination mitochondrial formulas available by reputable suppliers, and many contain more than one of the cofactors and coenzymes listed above.

One can consider mitochondrial support and supplementation in two senses, for regular supplementation, usually twice or three times a day, and also ad hoc supplementation, when one's mitochondrial function is especially poor, i.e. dips during the day particularly when one has overdone things. There are various symptoms for this, which may vary from individual to individual, according to the exact mitochondrial and endocrine/neurotransmitter imbalance pattern. However, for 'emergency' or ad hoc supplementation, I have found personally that a combination of Acetyl-L-Carnitine (or whichever Carnitine works for you), Coenzyme Q10, and Active B3 help to relieve such symptoms most effectively. If cardiac symptoms have also arisen, then the above will also help to support more efficient energy production to the heart, but one should then also consider taking (additional) Hawthorn. This is described on the Cardiac Insufficiency page. If you are especially worn out in a mitochondrial sense, rather than sleep cycle sense, late in the evening, it may well be a good idea to take some extra ad hoc mitochondrial supplements so that the body can function properly, and thus allow you to fall asleep. Otherwise you may find your biochemistry is too chaotic to promote the correct neurotransmitter production pathways for sleep. Try experimenting if this is something that affects you to see what works best for you.

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Supplemental ATP Replacement:

There are two methods of replacing lost ATP or to supplement the slow regeneration of ADP and AMP. This involves either consumption of a precursor to ATP, i.e. the sugar D-ribose, or to take micro-encapsulated ATP in the form of Peak ATP. These are discussed below.

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D-ribose:

D-ribose is an aldopentose, a monosaccharide (a sugar), a component part of DNA, RNA and ATP. ATP is made up of three main components, adenosine, and amino acid, three phosphate molecules, and D-ribose. It is believed that supplementation with D-ribose ensures that it is 'exclusively' directed by the body to produce more ATP, i.e. when ADP has been converted into AMP and cannot be recycled. Some patients have reported an energy boost followed by a sudden 'crash' in energy levels, which might suggest that it is being metabolised to some extent as a sugar, rather than a building material for ATP. Paul Cheney believes that in a small number of patients it seems to be converted to glucose and metabolised by both the patient and his bad bacteria (resulting in increased wind); ana also in a small number of patients, D-ribose is reputed to be metabolised anaerobically resulting in a build up of lactic acid in the body. However, the most common experience is of some ATP production benefit overall, according to Cheney. D-ribose is promoted by a number of other specialists in the field for CFS, ME and Fibromyalgia sufferers.

http://en.wikipedia.org/wiki/Ribose

'D-ribose has also been used to reduce fatigue in fibromyalgia and chronic fatigue syndrome. A 2006 study [by Teitelbaum, Johnson and St Cyr] concluded that D-ribose (
5 g three times a day) was effective in the treatment of FM and CFS. 66% of the 41 participants found the supplement helpful and it produced improvement in all the areas tested: energy, sleep, mental clarity, pain intensity and well-being. The study was not placebo controlled, however.'

www.ncbi.nlm.nih.gov/pubmed/17109576

www.endfatigue.com/tools-support/D-ribose.html

http://www.ei-resource.org/articles/chronic-fatigue-syndrome-articles/d%11ribose-treatment-of-chronic-fatigue-syndrome

I took 3 teaspoons of D-Ribose per day and over a period of a few months in the first quarter of 2009, beneficial effects were seen to have disappeared and it greatly contributed to the return of my bad bacteria and yeast. So not particularly successful. If one has been recommended D-ribose by one's practitioner, and/or has tested positively for it kinesiologically, then one should start out at a low dosage. If no beneficial effects are noticed in the short term, or when no more beneficial effects are noticed from taking it, one would be wise to desist from taking it, for the above reasons, as it may be causing more harm than good. Although it is widely hyped by some specialists in CFS and related disorders, I have only come across one person who experienced noticeably beneficial effects from taking it, of a small handful, the others simply noticed only a slight or no improvement.



Bioenergy Life Science are the manufacturers of 'BIOENERGY RIBOSE', the D-Ribose used by the most popular and highest quality supplement suppliers. Former known as Valen Labs, they launched the product in 2000, and subsequently changed their company name to Bioenergy Life Science in October 2006. 'BIOENERGY RIBOSE' is available capsule or powder form, but it makes more sense to take it in powder form, a teaspooon, in a small glass of water, for example, a couple of times a day. Bioenergy Life Science sell 'BIOENERGY RIBOSE' in their own branded product, Corvalen, which is also available as Corvalen M (with additional Magnesium and Malate). They also sell it under licence to other brands, and examples of other 100% 'BIOENERGY RIBOSE' D-ribose products include: Doctor's Best Best D-Ribose, Jarrow Formulas Ribose Muscle Edge, NOW Sports D-Ribose Powder and LifeExtension D-Ribose Powder. As all the above 'BIOENERGY RIBOSE' powder products are exactly the same, it may make most sense to buy the most cost effective brand, which is currently Doctor's Best (if purchased in/from the USA).

www.bioenergy.com

www.bioenergy.com/store/Main.aspx?html=ds&topic=b

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Peak ATP:



An additional way to support sufficient availability of ATP is to actually consume an ATP supplement, i.e. one that actually contains ATP, to directly replace that which is not there when it needs to be in the body's cells. This is more of an emergency or short term measure than a medium or long term strategy to an ATP deficit and mitochondrial dysfunction. One really should be looking to address the actual core reasons for mitochondrial dysfunction, and indeed ATP availability may only be part of the problem as can be seen above (i.e. ATP transport etc.) I have tried such a product, called 'Peak ATP'. Peak ATP is a form of enterically coated ATP (Adenosine 5'-Triphosphate Disodium) which is said not to be destroyed one's the stomach acid and is absorbed in the small intestine, and that which is absorbed in the blood stream can be directly be utilised by the body's cells as a readily available source of ATP (in lieu of the body's own sufficient production of fresh ATP and recyclying of ADP back to ATP). The efficiency of Peak ATP may also be dependent on one's digestive efficiency. Peak ATP is a trademarked product which is sold under licence by Solgar, Life Extension and MRM. It is also marketed under other brand names, such as Active ATP (MRM brand name). Other Mitochondrial supplements exist containing ATP, but it may be debated as to whether it is enterically coated or not and thus not simply destroyed in the stomach. I have tried the ATP products of all three manufacturers.

- Life Extension's PEAK ATP with GlycoCarn. Each tablet contains 100mg of Peak ATP and 500mg of GlycoCarn Glycine, a trademarked form of Propionyl-L-Carnitine Hydrochloride.

- Solgar PEAK ATP; or Solgar PEAK ATP with CoQ-10. The former product is cheaper than the latter. Both contain 125mg of PEAK ATP.

- MRM Biosorb Active ATP2. MRM BioSorb Active ATP2 is in chewable tablet form, and appears to be the most cost effective form of Peak ATP (Solgar's being 2nd cheapest). It contains 125mg of PEAK ATP and also contains 200mg of B-Alanine Peptide per tablet. It may not be suitable for those who have too high Beta-Alanine levels already, or if taken too regularly. It is quite a pleasant product to chew whereas the other two above if chewed are quite vile tasting and leaving a large blob of Magnesium Stearate (almost like chewing gun) afterwards, which is probably better spat out.

The Peak ATP web site can be seen below for further information regarding specifications and ATP related-research (although not specific to Peak ATP).

www.peakatp.com

Peak ATP seems to have made the most difference initially in terms of increased energy levels. I felt a huge rush, and warm sense of well being that lasted several hours after taking it. This sensation died down after a few days of taking it, and after a week, I felt that the product when taken, made a slight difference to my energy levels, but that sense of euphoria was nowhere to be felt, or ever so slightly, depending on a number of internal factors that may have come into play at the moment of taking it. Much larger doses were required to gain at least some of the initial effect back again. However, I felt it did provide more of an instant noticeable effect than taking D-ribose. The supplement works best when chewed in the mouth rather than swallowed, and hence absorbed more quickly, although this was a little disgusting! To what extent is the body getting adapting to the supplement and compensating by producing less ATP itself? And to what extent is the body simply getting used to it and largely learning to ignore it? One could argue that taking in replacement ATP would require much larger quantities in any case to have any effect, taking into account that the average person turns over his own body weight in ATP per day. How much would be enough? Perhaps this could be applied to some extent to ATP precursors like D-Ribose. This doesn't however explain the very positive initial effects I had with Peak ATP. It is also worth considering that taking ATP precursors or replacements is better whilst one still has energy rather than after one has 'burnt out' and used up all one's ATP and converted much of one's ADP to AMP. i.e. as a preventative measure to 'stop you rolling off the top of the hill' rather than trying to recover from a place 'at the bottom of the hill'. I first took it at a time when (according to blood/urine tests) my levels of cofactors and coenzymes were sufficient/borderline, and when I was already supplementing a wide range of other cofactors and coenzymes (perhaps gratuitously). To identify the best way of boosting your mitochondrial function in the short term requires laboratory testing and a skilled practitioner.

As I found out, it is easy to become dependent on Peak ATP, however, it is easy to keep increasing the dosages to maintain the same effect. Peak ATP by its nature seems to provide a quick 'fix', but is also followed an hour or two later by a low (predisposing one to taking some more), whereas without taking Peak ATP one may feel a more consistent level of energy. Taking Peak ATP does seem to shift the nature of one's mitochondrial function to some degree, not necessarily for the better. As stated above, however, it is useful in cases where one's mitochondrial function is so poor that one is experiencing chest pains (i.e. of a cardiac nature) or extreme shortness of breath or energy that is preventing one from sleeping. It can be useful to take also when one is having a particularly exhausting day, to keep one going, as a temporary measure. But like many crutches, one can become used to taking it regularly, and it may temporarily prevent the long term progress and recovery of one's natural mitochondrial function.

One particular negative thing that can be said about Peak ATP (which equally applies to D-ribose above) is that, apart from not really addressing the problems associated with mitochondrial function such as electron transfer and ATP transport, it does seem to potentially contribute to dysbiosis. I found that over a few months of taking both D-ribose and Peak ATP (the latter in very large quantities, perhaps because I was not taking much Acetyl-L-Carnitine or Coenzyme Q10), my dysbiosis which I had previously rectified came back with a vengeance, in particular, bad bacteria and yeast. One could assume that because Peak ATP is swallowed in tablet form, or even when chewed, a significant amount makes its way down to the colon, where it can directly fuel the bad bacteria (together with other nutrients in the stool that they require to feed). In addition, there may well be a significant amount of bad bacteria and fungus in the bloodstream and tissues, and this may also be directly assisted by taking peak ATP. The ATP the body naturally creates should be floating around the bloodstream of course, but the majority should remain within the cells where it is created. Taking a form of supplemental ATP means most of this floats around in the blood or digestive tract before it is actually absorbed by cells, so it is more likely to potentially result in dysbiosis. This is not such an issue if one is taking small amounts, but if large amounts are taken, then one should consider the consequences and indeed the reason why one needs to take this much, as it points to a severe problem in other areas of mitochondrial function, e.g. ATP transport, or electron transfer, B vitamin deficiency, krebs cycle cofactor bottlenecks, or mitochondrial membrane integrity, which if addressed would probably provide more benefit than the ultra-high dosages of Peak ATP.

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Relevant Tests:

A urine test such as the Metabolic Analysis Profile by Genova Diagnostics, for example, would highlight which exact metabolites or co-factors are out of balance. Blood tests, for example, a Mitochondrial Membrane - Translocator Protein Study and ATP Profile by Acumen, would highlight the health of the mitochondrial membrane and the level of ADP to ATP efficiency. Please see the links page for contact details of these and other laboratories. In addition, a therapy working on the body's energetic (qi) system may help. Such therapies are outlined on the energetic therapies page.

Please see the digestive disorders page for information about improper conversion of amino acids. And please see the hormonal deficiencies page for information about metabolic rate and basal temperature measurement.

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