Article: Post Exertional Malaise IV: Power to the People by Jennifer Spotila, J.D.
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(This is a repost of a comment I made on Part III of Jen's series of articles on PEM in CFS.)
Hi, Jen.
I enjoyed your articles on PEM.
I would like to enlarge a little on the cardiovascular/energy system aspect that you mentioned.
The observed low oxygen consumption, high lactate and oxidative stress in CFS all point to problems with the mitochondria. There is abundant evidence for mito dysfunction in CFS. The most direct evidence is the work of Dr. John McLaren Howard of AcumenLab in the UK. Some of this was described in the paper by Myhill, Booth and Howard showing a correlation between lab measures of mito dysfunction and degree of disability in CFS patients.
Mito dysfunction can easily explain the basic physical and mental fatigue, as well as the diastolic dysfunction of the heart in CFS.
To explain PEM on the basis of a mito dysfunction issue requires a mechanism that worsens the mito dysfunction as a result of placing greater demands on the mitochondria. I'm aware of two possible explanations that have been suggested:
The first is the one embodied in the book by Dr. Stephen Sinatra, called The Sinatra Solution. This explanation has been applied to CFS by Dr. Sarah Myhill. The idea is that when high demand is placed on the mitochondria for ATP, and the mitochondria are not able to keep up with this demand, some of the ADP reacts with other ADP, producing ATP plus AMP. This supplies some ATP temporarily, but the AMP breaks down to adenosine and exits from the cell. Thus, the cell has to start from scratch to build new ADP, and this is a slow process, requiring synthesis of D-ribose. This time lag is what gives rise to the PEM under this hypothesis.
The second is one I suggested several years ago, and I think it may still have some viability. The idea is that the mitos are in a state of oxidative stress, as we know. In my hypothesis, this is due to depletion of glutathione. Others have different views as to the cause of the oxidative stress, including Prof. Pall and Dr. Cheney. Nevertheless, I think we agree that there is oxidative stress, as has been shown by many measurements. It is known that the most vulnerable molecules in the mitochondria to oxidative stress are the unsaturated fatty acids in the phospholipid membranes of the mitochondria. These membranes are very important to the production of ATP, because this is carried out by enzymes that are embedded in these membranes. When higher demands for ATP are placed on the mitochondria, the state of oxidative stress worsens, because oxidizing free radicals are a normal product of metabolism, and higher the metabolic rate, the higher the oxidative stress, when glutathione is depleted and thus the antioxidant enzyme system is dysfunctional. I have suggested that this extra demand thus produces more damage to the mito membranes. The cells are able to repair this damage, at least to some extent, but this takes time. I suggest that that delayed repair process could account for PEM, and that this would be consistent with other things we know about the mitochondria in CFS.
Anyway, thank you for writing about a very important aspect of CFS, and I hope your effort attracts more attention to this aspect of CFS, because I think it holds the key to developing a better understanding of this disorder.
Best regards,
Rich Van Konynenburg
Hi, Jen.
I enjoyed your articles on PEM.
I would like to enlarge a little on the cardiovascular/energy system aspect that you mentioned.
The observed low oxygen consumption, high lactate and oxidative stress in CFS all point to problems with the mitochondria. There is abundant evidence for mito dysfunction in CFS. The most direct evidence is the work of Dr. John McLaren Howard of AcumenLab in the UK. Some of this was described in the paper by Myhill, Booth and Howard showing a correlation between lab measures of mito dysfunction and degree of disability in CFS patients.
Mito dysfunction can easily explain the basic physical and mental fatigue, as well as the diastolic dysfunction of the heart in CFS.
To explain PEM on the basis of a mito dysfunction issue requires a mechanism that worsens the mito dysfunction as a result of placing greater demands on the mitochondria. I'm aware of two possible explanations that have been suggested:
The first is the one embodied in the book by Dr. Stephen Sinatra, called The Sinatra Solution. This explanation has been applied to CFS by Dr. Sarah Myhill. The idea is that when high demand is placed on the mitochondria for ATP, and the mitochondria are not able to keep up with this demand, some of the ADP reacts with other ADP, producing ATP plus AMP. This supplies some ATP temporarily, but the AMP breaks down to adenosine and exits from the cell. Thus, the cell has to start from scratch to build new ADP, and this is a slow process, requiring synthesis of D-ribose. This time lag is what gives rise to the PEM under this hypothesis.
The second is one I suggested several years ago, and I think it may still have some viability. The idea is that the mitos are in a state of oxidative stress, as we know. In my hypothesis, this is due to depletion of glutathione. Others have different views as to the cause of the oxidative stress, including Prof. Pall and Dr. Cheney. Nevertheless, I think we agree that there is oxidative stress, as has been shown by many measurements. It is known that the most vulnerable molecules in the mitochondria to oxidative stress are the unsaturated fatty acids in the phospholipid membranes of the mitochondria. These membranes are very important to the production of ATP, because this is carried out by enzymes that are embedded in these membranes. When higher demands for ATP are placed on the mitochondria, the state of oxidative stress worsens, because oxidizing free radicals are a normal product of metabolism, and higher the metabolic rate, the higher the oxidative stress, when glutathione is depleted and thus the antioxidant enzyme system is dysfunctional. I have suggested that this extra demand thus produces more damage to the mito membranes. The cells are able to repair this damage, at least to some extent, but this takes time. I suggest that that delayed repair process could account for PEM, and that this would be consistent with other things we know about the mitochondria in CFS.
Anyway, thank you for writing about a very important aspect of CFS, and I hope your effort attracts more attention to this aspect of CFS, because I think it holds the key to developing a better understanding of this disorder.
Best regards,
Rich Van Konynenburg
Wow. What a disappointment this turned out to be. I have to say that I'm very disappointed in seeing pacing recommended here as a treatment for PEM especially after all the info on the web now. This simply isn't an exceptable answer and has no scientific basis whatsoever. Just imagine, if the people who make our cell phones thought this way, we'd never get a connection. ; )
Hi Rich,
Thanks for giving an intelligent approach to what may be causing PEM. Any chance of getting Myhill, Cheney, Pacific Labs, and others with biochemical expertise involved in a think tank on what to do about PEM ? I just got my NutrEval test results back so this may help ... I'm still working on understanding these before I post them. They're interesting to say the least.
BTW. Pacing IS NOT an option for me. I would describe pushing myself past the point of feeling comfortable as "getting the lead out" and can relate it to when I used to be healthy and only needed to push myself to get moving again. I did aerobics for years ... I can push past my comfort zone and have to everytime I get out to go grocery shopping or cook something that requires an hour or so. When I push past what feels like my normal ATP usage, I feel shakey for a bit then my energy level recovers and I feel normal again for a short period but this feeling keeps coming back. At some point, I no longer feel "normal" but can push myself still. I have to if I want to eat ...
I "think" this has something to do with glucose / ketone usage as over time I've increased my stamina. As an example, I used to have petite mals everytime I washed my car or did anything that required this type of exertion, but now I'm usually ok ... If I have PEM, I can't work at this level period.
I'm sure my improvement thusfar is related to my body utilizing glucose and ketones more efficiently all because of the Paleo / low carb diet I've been on for several years now. My GTT is much better ... hmm, however, I show that I'm over producing insulin at this point too. I know this is at least part of what's causing me to have chronic hypoglycemia now ... Dr. Myhill recommends the Paleo diet to her patients because of chronic hypoglycemia ...
thanks again ... I'm looking forward to more info on PEM ... X
Hi Rich,
Thanks for giving an intelligent approach to what may be causing PEM. Any chance of getting Myhill, Cheney, Pacific Labs, and others with biochemical expertise involved in a think tank on what to do about PEM ? I just got my NutrEval test results back so this may help ... I'm still working on understanding these before I post them. They're interesting to say the least.
BTW. Pacing IS NOT an option for me. I would describe pushing myself past the point of feeling comfortable as "getting the lead out" and can relate it to when I used to be healthy and only needed to push myself to get moving again. I did aerobics for years ... I can push past my comfort zone and have to everytime I get out to go grocery shopping or cook something that requires an hour or so. When I push past what feels like my normal ATP usage, I feel shakey for a bit then my energy level recovers and I feel normal again for a short period but this feeling keeps coming back. At some point, I no longer feel "normal" but can push myself still. I have to if I want to eat ...
I "think" this has something to do with glucose / ketone usage as over time I've increased my stamina. As an example, I used to have petite mals everytime I washed my car or did anything that required this type of exertion, but now I'm usually ok ... If I have PEM, I can't work at this level period.
I'm sure my improvement thusfar is related to my body utilizing glucose and ketones more efficiently all because of the Paleo / low carb diet I've been on for several years now. My GTT is much better ... hmm, however, I show that I'm over producing insulin at this point too. I know this is at least part of what's causing me to have chronic hypoglycemia now ... Dr. Myhill recommends the Paleo diet to her patients because of chronic hypoglycemia ...
thanks again ... I'm looking forward to more info on PEM ... X
Pacing definitely does reduce my symptoms - actually pretty dramatically. I am in a world of pain if I exercise too much. It certainly isn't a cure - it just leads to some improvement in cognitive function and increased QOL....PEM is the key issue for me and I hope that whatever happens with XMRV that researchers focus on it heavily.
I definitely hope we can get more research into mitochondria and Rich's model.
I definitely hope we can get more research into mitochondria and Rich's model.
hi rich, Have u had anyone use creatine with any success. From my understanding creatine works with adp to form atp again, helps to recycle these nutrients. From what i have read about others with cfs, the cfsers that can exercise seem to prefer anaerobic type exercises, so im wondering if its mainly our aerobic metabolism thats dysfunctional. Tight muscles and lack of endurance can improve with creatine has in helps anaerobic pathways to keep producing energy longer and reduce waste products of anaerobic metabolism. Im one of those cfsers that can exercise to some degree but even light aerobic stuff like walking can leave me feeling exhausted but low repetition weight lifting isnt too much of a problem. Pre cfs was a reasonable weight lifter and can still lift quite heavy weights(muscle memory helps) but limit the duration etc and when training i dont do things that leave me out of breath, that why i think its our ability to functional aerobically thats gone. Also i wonder if exercising anaerobically can help reduce any PEM, but there are two energy systems in anaerobic metabolism, phosocreatine lasting approx 10 seconds and lactate system lasting up to 2 min. i think exercising using the phoso creatine is what cfsers can do as this energy is recovered from very quickly, within 2 minutes. Bit off the track but creatine supplements can help boths these anaerobic systems last longer and or recover quicker. I have used creatine with some success but noticed nothing from ribose supplements.
Any thoughts on this Rich, im suprised i can remember this stuff from physical education at school, correct me if im wrong anywhere.
cheers!!!
Any thoughts on this Rich, im suprised i can remember this stuff from physical education at school, correct me if im wrong anywhere.
cheers!!!
Hi, heapsreal.
I'd say your memory for this stuff is really good!
With respect to creatine, yes, it serves as a reservoir for energetic phosphate groups, and helps both to conduct and to store energy in the cells, as it is able to receive phosphate groups from ATP and give them to ADP.
It's important in both the muscles and the brain. The production of creatine is the main user of methylation in the body, and it is deficient in PWMEs/PWCs, as evidenced frequently by low 24-hour excretion of creatinine, which is the breakdown product of creatine. This is to be expected because of the partial block in the methylation cycle.
Does it help to supplement creatine? Theoretically, I would expect that it would help to extend endurance a little bit, but not a whole lot. I think this generally agrees with what a few people who have tried supplementing it have reported.
The difference between anaerobic and aerobic exercise, from the standpoint of ATP, is that aerobic exercise requires ATP at a higher rate than does anaerobic exercise. The reason is that the number of muscle contractions per unit time is higher with aerobic exercise. Every time a muscle fiber contracts, it requires an ATP molecule to enable it to relax to be ready for the next contraction. If it just stays contracted, such as in weight lifting, it doesn't require as much ATP.
In ME/CFS, because of glutathione depletion and the buildup of toxins and other effects that result from it, the Krebs cycle and the respiratory chain in the mitochondria are partially blocked. This limits the ability of the mitochondria to perform aerobic metabolism to produce ATP. The cells therefore must rely more on glycolysis.
The solution to these problems, in my opinion, is to treat to lift the partial block in the methylation cycle, which allows glutathione to come up to normal, and that will correct the dysfunction of the mitochondria. Normal methylation cycle function will also allow normal production of creatine, as well as normal production of carnitine and coenzyme Q-10, which are also needed by the mitochondria.
Best regards,
Rich
I'd say your memory for this stuff is really good!
With respect to creatine, yes, it serves as a reservoir for energetic phosphate groups, and helps both to conduct and to store energy in the cells, as it is able to receive phosphate groups from ATP and give them to ADP.
It's important in both the muscles and the brain. The production of creatine is the main user of methylation in the body, and it is deficient in PWMEs/PWCs, as evidenced frequently by low 24-hour excretion of creatinine, which is the breakdown product of creatine. This is to be expected because of the partial block in the methylation cycle.
Does it help to supplement creatine? Theoretically, I would expect that it would help to extend endurance a little bit, but not a whole lot. I think this generally agrees with what a few people who have tried supplementing it have reported.
The difference between anaerobic and aerobic exercise, from the standpoint of ATP, is that aerobic exercise requires ATP at a higher rate than does anaerobic exercise. The reason is that the number of muscle contractions per unit time is higher with aerobic exercise. Every time a muscle fiber contracts, it requires an ATP molecule to enable it to relax to be ready for the next contraction. If it just stays contracted, such as in weight lifting, it doesn't require as much ATP.
In ME/CFS, because of glutathione depletion and the buildup of toxins and other effects that result from it, the Krebs cycle and the respiratory chain in the mitochondria are partially blocked. This limits the ability of the mitochondria to perform aerobic metabolism to produce ATP. The cells therefore must rely more on glycolysis.
The solution to these problems, in my opinion, is to treat to lift the partial block in the methylation cycle, which allows glutathione to come up to normal, and that will correct the dysfunction of the mitochondria. Normal methylation cycle function will also allow normal production of creatine, as well as normal production of carnitine and coenzyme Q-10, which are also needed by the mitochondria.
Best regards,
Rich
Thanks for that rich. Do u have an opinion on whether virus like ebv/cmv function aerobically and maybe 'steeling' our ATP and for that matter bacterial infections as well?
Hi, heapsreal.
You're welcome.
Viruses don't actually carry on energy metabolism themselves. They act as parasites on the energy metabolism of our cells. It's true that viruses such as EBV and CMV do use ATP when they take over our cells' protein-making machinery to make their own proteins. They can also cause our cells to die. These viruses are able to become activated when the ratio of reduced to oxidized glutathione drops too low in the cells, so that the cystine disulfide bonds in glycoprotein B can form, and when methylation is not sufficient to keep the viral genes silenced. So again, it comes down to lifting the partial block in the methylation cycle, which allows glutathione to come back up. This will put the viruses back into their latent (nonactive) state.
Bacteria do carry on energy metabolism. Some do aerobic metabolism, some to anaerobic, and some can function either way. The main bacterial infections found in ME/CFS are due to intracellular bacteria, such as mycoplasma, chlamydia and rickettsia. These again act as parasites inside our cells. Getting glutathione up and thus getting oxidative stress down will probably shut these bacterial infections down, too.
Best regards,
Rich
You're welcome.
Viruses don't actually carry on energy metabolism themselves. They act as parasites on the energy metabolism of our cells. It's true that viruses such as EBV and CMV do use ATP when they take over our cells' protein-making machinery to make their own proteins. They can also cause our cells to die. These viruses are able to become activated when the ratio of reduced to oxidized glutathione drops too low in the cells, so that the cystine disulfide bonds in glycoprotein B can form, and when methylation is not sufficient to keep the viral genes silenced. So again, it comes down to lifting the partial block in the methylation cycle, which allows glutathione to come back up. This will put the viruses back into their latent (nonactive) state.
Bacteria do carry on energy metabolism. Some do aerobic metabolism, some to anaerobic, and some can function either way. The main bacterial infections found in ME/CFS are due to intracellular bacteria, such as mycoplasma, chlamydia and rickettsia. These again act as parasites inside our cells. Getting glutathione up and thus getting oxidative stress down will probably shut these bacterial infections down, too.
Best regards,
Rich
The experience of a number people is that if you can get biotoxin exposures low enough, the PEM goes away totally.
Extreme avoidance isn't enough to resolve every CFS symptom. The cognitive ones are much harder to fix.
But the PEM is pretty easy to get under control. If you call extreme avoidance easy!
Actually, even when I was living in the moldy house, I unknowingly took advantage of this effect. I would go to the Chicago Botanic Garden, which I later realized was the best place around in terms of the outside air. I'd rest for a couple of hours. Then I was able to walk around for an hour or so, spontaneously, without PEM afterwards.
This despite the fact that climbing half a flight of stairs in the moldy house was enough to do me in.
Anyway, toxic mold exercises most of its damage through oxidative stress. So this would be consistent with Rich's hypothesis, no?
Best, Lisa
Extreme avoidance isn't enough to resolve every CFS symptom. The cognitive ones are much harder to fix.
But the PEM is pretty easy to get under control. If you call extreme avoidance easy!
Actually, even when I was living in the moldy house, I unknowingly took advantage of this effect. I would go to the Chicago Botanic Garden, which I later realized was the best place around in terms of the outside air. I'd rest for a couple of hours. Then I was able to walk around for an hour or so, spontaneously, without PEM afterwards.
This despite the fact that climbing half a flight of stairs in the moldy house was enough to do me in.
Anyway, toxic mold exercises most of its damage through oxidative stress. So this would be consistent with Rich's hypothesis, no?
Best, Lisa
Hi Rich, im going to keep racking your brain abit. I dont follow a formal treatment for mythlation cycle block, sort of stumbled over supplements that have helped and seem to be ones you recommend. I am a fan of NAC as i use it for its liver protection effects as i take paracetamol/tylenol regularly(which NAC is the antidote for overdose of these meds) as well from other medications and the rise in glutathione and antioxdant protection as a bonus. Im also a fan of lipoic acid as its suppose to recycle other antioxidants and its good for glucose metabolism, does lipoic acid have an effect on the methylation cycle? I understand b12 and folates are a big part of methylation, i have have access to an injectable formula which has 500micrograms hydroxycobalamin and 15mg of folic acid per ml. Would u recommend such a formula, dosage and frequency wise?
Also im on the antiviral famvir at 250mg twice a day, but i got wondering about the life cycle of viruses, so in my case it appears cmv is the culprit. also antivials have a short half life like 4 hours, although have read famvir has a longer intracellular life span of maybe 8. so if it takes cmv more then 24 hours to replicate, i may only need antiviral doses once a day, or may need to take more regularly dosing. Rich do u have info on the life cycle of cmv, ebv, hhv6 and any further opinions on dosing antivirals.
cheers!!! your info is appreciated
Also im on the antiviral famvir at 250mg twice a day, but i got wondering about the life cycle of viruses, so in my case it appears cmv is the culprit. also antivials have a short half life like 4 hours, although have read famvir has a longer intracellular life span of maybe 8. so if it takes cmv more then 24 hours to replicate, i may only need antiviral doses once a day, or may need to take more regularly dosing. Rich do u have info on the life cycle of cmv, ebv, hhv6 and any further opinions on dosing antivirals.
cheers!!! your info is appreciated
Hi, heapsreal.
NAC is O.K. so long as there isn't a high mercury burden in the body, because NAC can move mercury into the brain, as shown by experiments in rats. If there is a significant burden of heavy metals, Dr. David Quig of Doctor's Data Lab has recommended limiting the NAC dosage to 300 mg per day.
Lipoic acid does offer the advantages you noted. Again, it's O.K. unless there is a significant mercury load. If that's the case, lipoic acid can mobilize mercury. Andy Cutler's treatment for mercury toxicity involves taking lipoic acid at certain intervals in time in order to keep its concentration up, so that it does not mobilize mercury and then drop it, so that it goes elsewhere in the body and causes more problems.
Lipoic acid will affect the methylation cycle indirectly, by helping to lower the state of oxidative stress, by supporting the antioxidant network. The cobalt ion in the cobalalamin serving as a coenzyme for methionine synthase in the methylation cycle is redox-sensitive. Prof. Dick Deth has pointed out that it is the main redox sensor in the cell, and it normally governs how much homocysteine is recycled back to methionine, vs. how much is directed into the transsulfuration pathway, some of which goes into glutathione synthesis.
I think you must mean 15 micrograms of folic acid per milliliter, rather than milligrams, but I don't know that for sure. I know that the Vinitsky protocol does use a lot of folic acid. I believe that hydroxocobalamin is a good form of B12 for many PWCs, and it is the form included in the simplified treatment approach that I have suggested. Some people do better with methylcobalamin, depending on their genomic polymorphisms and their methylation status. As you may know freddd on this forum recommends using methylcobalamin and adenosylcobalamin.
I prefer the chemically reduced forms of folate rather than folic acid. Some people are not able to use folic acid very well. In order to get the methylation cycle up and running properly, 5-methyl tetrahydrofolate is needed. The conversion from folic acid to 5-MTHF can be difficult, as it requires four sequential biochemical reactions, and there can be polymorphisms in the enzymes that catalyze these reactions: DHFR, SHMT and MTHFR.
On the other hand, the proof is in the pudding. If this combination works for an individual, that's great.
I don't know much about viral life cycles or antiviral dosing.
Best regards,
Rich
NAC is O.K. so long as there isn't a high mercury burden in the body, because NAC can move mercury into the brain, as shown by experiments in rats. If there is a significant burden of heavy metals, Dr. David Quig of Doctor's Data Lab has recommended limiting the NAC dosage to 300 mg per day.
Lipoic acid does offer the advantages you noted. Again, it's O.K. unless there is a significant mercury load. If that's the case, lipoic acid can mobilize mercury. Andy Cutler's treatment for mercury toxicity involves taking lipoic acid at certain intervals in time in order to keep its concentration up, so that it does not mobilize mercury and then drop it, so that it goes elsewhere in the body and causes more problems.
Lipoic acid will affect the methylation cycle indirectly, by helping to lower the state of oxidative stress, by supporting the antioxidant network. The cobalt ion in the cobalalamin serving as a coenzyme for methionine synthase in the methylation cycle is redox-sensitive. Prof. Dick Deth has pointed out that it is the main redox sensor in the cell, and it normally governs how much homocysteine is recycled back to methionine, vs. how much is directed into the transsulfuration pathway, some of which goes into glutathione synthesis.
I think you must mean 15 micrograms of folic acid per milliliter, rather than milligrams, but I don't know that for sure. I know that the Vinitsky protocol does use a lot of folic acid. I believe that hydroxocobalamin is a good form of B12 for many PWCs, and it is the form included in the simplified treatment approach that I have suggested. Some people do better with methylcobalamin, depending on their genomic polymorphisms and their methylation status. As you may know freddd on this forum recommends using methylcobalamin and adenosylcobalamin.
I prefer the chemically reduced forms of folate rather than folic acid. Some people are not able to use folic acid very well. In order to get the methylation cycle up and running properly, 5-methyl tetrahydrofolate is needed. The conversion from folic acid to 5-MTHF can be difficult, as it requires four sequential biochemical reactions, and there can be polymorphisms in the enzymes that catalyze these reactions: DHFR, SHMT and MTHFR.
On the other hand, the proof is in the pudding. If this combination works for an individual, that's great.
I don't know much about viral life cycles or antiviral dosing.
Best regards,
Rich
I have eliminated Post Extertional Malaise with Magnesium and Taurine shots
I see Dr. Sharp who works with Cheney and have followed their advice to take magnesium and taurine shots when I have overdone things physically and can feel the post malaise coming on. This has eliminated my post extertional malaise completely. I am doing better with no more set backs.
I see Dr. Sharp who works with Cheney and have followed their advice to take magnesium and taurine shots when I have overdone things physically and can feel the post malaise coming on. This has eliminated my post extertional malaise completely. I am doing better with no more set backs.
I didn't notice before that the first article had turned into a series. Taken together, this series is the best source of information on PEM I've seen to date.