Exercise, glutathione and inflammatory response

[Marco]

Assuming some of our mitochondria are still functioning, would it be beneficial to stimulate mitochondrial biogenesis by either stimulating the SIRT/PPAR pathways and/or by light exercise of muscles with a high concentration of mitochondria (such as calf muscles). Would the latter induce mitochondrial biogenesis globally or only locally?

Is there any possibility that a combination of gluauthione supplementation plus mito biogenesis by whatever means might reach a level sufficient to overcome the vicious circle?

I'm glad to see that this approach is at least being trialled :

Chronic Fatigue Syndrome: A Presumptive Mitochondrial Disorder (CFS:M)

A placebo-controlled trial will be undertaken in 24 CFS patients aged 25-55. Patients fulfilling the CDC criteria for CFS will participate in this 6 month study. Other medical causes for fatigue will be excluded. Half the patients will receive treatment consisting of daily conditioning exercise plus nutraceutical supplements (ENT), that has been shown to be beneficial for patients with mitochondrial dysfunction, while the other half will receive daily conditioning exercise and placebo tablets. Response to ENT will be evaluated by maximum oxygen consumption (VO2max) and circulating lactate levels during & after treadmill exercise, a 6-minute walk test, and a fatigue questionnaire. In addition, whether ENT corrects the elevated brain cerebrospinal fluid levels and decreased brain glutathione levels will be measured. To ensure compliance to therapy patients will be monitored frequently. The objective of this study is to assess the safety and efficacy of ENT and whether ENT leads to sustained improvement of CFS patients compared to their baseline status, and compared to an exercised group of patients not receiving supplements.

http://clinicaltrials.gov/ct2/show/NCT01471652?term=chronic+fatigue+syndrome&rank=12

 

[richvank]

Hi, Marco.

I'm glad to see that mito dysfunction in ME/CFS is to be the topic of a clinical trial, too. Thank you for posting this.

However, unfortunately this study as it is currently described will not address the vicious circle mechanism that I believe holds glutathione down and initiates the mito dysfunction in ME/CFS.
I have just emailed the Principal Investigator concerning this issue. Since the study has not yet begun, perhaps there is an opportunity to add to the list of supplements.

Best regards,

Rich

 

[Marco]

Hi, Marco.

I'm glad to see that mito dysfunction in ME/CFS is to be the topic of a clinical trial, too. Thank you for posting this.

However, unfortunately this study as it is currently described will not address the vicious circle mechanism that I believe holds glutathione down and initiates the mito dysfunction in ME/CFS.
I have just emailed the Principal Investigator concerning this issue. Since the study has not yet begun, perhaps there is an opportunity to add to the list of supplements.

Best regards,

Rich

Good idea Rich although I'm at a loss to understand why these interventions might help with a congential genetic mitochondrial disease and not with us?

I also wonder would they consider trying some of the PPAR (PGC1 alpha) stimulants such a quercetin (which would of course introduce too many variables into the experimental design).

 

[richvank]

Good idea Rich although I'm at a loss to understand why these interventions might help with a congential genetic mitochondrial disease and not with us?

I also wonder would they consider trying some of the PPAR (PGC1 alpha) stimulants such a quercetin (which would of course introduce too many variables into the experimental design).

Hi, Marco.

I think these supplements will help to some degree. Dr. Myhill has used some of them in her mitochondrial package, and she has seen improvements. What I refer to is getting at the root of the mitochondrial problem so that it can be totally corrected, rather than just helped to some degree.

I think your suggestion about PPAR stimulants is interesting. However, my concern about this is that if the glutathione depletion is not corrected by lifting the partial methylation cycle block, the new mitochondria are likely to suffer from the same problem as the older ones. The glutathione depletion in ME/CFS is systemic, as shown by the low levels in the plasma.

Best regards,

Rich

 

[Marco]

I think your suggestion about PPAR stimulants is interesting. However, my concern about this is that if the glutathione depletion is not corrected by lifting the partial methylation cycle block, the new mitochondria are likely to suffer from the same problem as the older ones. The glutathione depletion in ME/CFS is systemic, as shown by the low levels in the plasma.

Best regards,

Rich

If you think there may be merit it exploring this as part of your protocol Rich (albeit perhaps as a temporary adjunct) there is a rich literature on PGC1 alpha and mitochondrial dysfunction.

This is a good overview :

PGC-1? activation as a therapeutic approach in mitochondrial disease

http://onlinelibrary.wiley.com/doi/10.1002/iub.261/full

Its been a few months since I was looking into this but there are a number of compounds that act as PCG1 alpha agonists (quercetin, resveratrol, oregano plus one other more potent compound that I've forgotten for the time being) pharmaceuticals (certain types of type II diabetes drugs) plus physiological (endurance exercise; cold stress).

... plus Nicotinic acid may be as effective in activating PGC1 alpha as exercise :

http://www.ncbi.nlm.nih.gov/pubmed/15525607

.. and I thought this was interesting given that there is an ongoing study at present which claims and association between staph infection and ME/CFS :

Mitochondrial Biogenesis Restores Oxidative Metabolism during Staphylococcus aureus Sepsis

http://171.66.122.149/cgi/content/full/ajrccm;176/8/768

 

[MDL]

We need a new paradigm here, and H2S is it

The missing link and underlying mechanism in ME most likely, is hydrogen sulfide. It can explain most findings in the disease. As you can see from my hypothesis http://www.cfids-cab.org/MESA/Lemle.pdf, I mentioned glutathione and its connection to sulfur metabolism, but I also mentioned bacteria, genes, diet and mitochondria. Hydrogen sulfide actually increases the production of glutathione, so if you are going to address glutathione, you can only do so by looking at sulfur metabolism.

 

[richvank]

If you think there may be merit it exploring this as part of your protocol Rich (albeit perhaps as a temporary adjunct) there is a rich literature on PGC1 alpha and mitochondrial dysfunction.

This is a good overview :

PGC-1? activation as a therapeutic approach in mitochondrial disease

http://onlinelibrary.wiley.com/doi/10.1002/iub.261/full

Its been a few months since I was looking into this but there are a number of compounds that act as PCG1 alpha agonists (quercetin, resveratrol, oregano plus one other more potent compound that I've forgotten for the time being) pharmaceuticals (certain types of type II diabetes drugs) plus physiological (endurance exercise; cold stress).

... plus Nicotinic acid may be as effective in activating PGC1 alpha as exercise :

http://www.ncbi.nlm.nih.gov/pubmed/15525607

.. and I thought this was interesting given that there is an ongoing study at present which claims and association between staph infection and ME/CFS :

Mitochondrial Biogenesis Restores Oxidative Metabolism during Staphylococcus aureus Sepsis

http://171.66.122.149/cgi/content/full/ajrccm;176/8/768

Hi, Marco.

Thanks for these links. I'll take a look at them. I note that the Life Extension Foundation www.lef.org is promoting this, also. They are now supplying a supplement called "BioPPQ":

http://www.lef.org/Vitamins-Supplements/Item01500/PQQ-Caps-with-BioPQQ.html

"BioPPQ" is supposed to promote biogenesis of new mitochondria. I haven't heard from anyone with ME/CFS who has tried this, so I don't know whether it would be beneficial in ME/CFS or not. As I noted earlier, I do have reservations about glutathione depletion being systemic, and I suspect that unless it is corrected, new mitochondria will be subject to it as well as the older ones.

Best regards,

Rich

 

[richvank]

The missing link and underlying mechanism in ME most likely, is hydrogen sulfide. It can explain most findings in the disease. As you can see from my hypothesis http://www.cfids-cab.org/MESA/Lemle.pdf, I mentioned glutathione and its connection to sulfur metabolism, but I also mentioned bacteria, genes, diet and mitochondria. Hydrogen sulfide actually increases the production of glutathione, so if you are going to address glutathione, you can only do so by looking at sulfur metabolism.

Hi, MDL.

I think you might be interested in the work of Dr. Stephanie Seneff of MIT. She is also working on the sulfur metabolism, and she has some out-of-the-box ideas. There is another thread here about her work, and there is a good interview of her by Dr. Mercola cited on the thread, also. I have been in contact with her, and I mentioned your paper to her and sent her the reference to it. Last week she gave a long seminar at the Weston Price conference in Dallas, and she has a paper coming out in Medical Hypotheses soon entitled "Might cholesterol sulfate deficiency contribute to the development of autistic spectrum disorder?"

Best regards,

Rich

 

[MDL]

Hi, MDL.

I think you might be interested in the work of Dr. Stephanie Seneff of MIT. She is also working on the sulfur metabolism, and she has some out-of-the-box ideas. There is another thread here about her work, and there is a good interview of her by Dr. Mercola cited on the thread, also. I have been in contact with her, and I mentioned your paper to her and sent her the reference to it. Last week she gave a long seminar at the Weston Price conference in Dallas, and she has a paper coming out in Medical Hypotheses soon entitled "Might cholesterol sulfate deficiency contribute to the development of autistic spectrum disorder?"

Best regards,

Rich

Hi Rich,

My two hypothesis papers made their way through the alternative community, so I'd be surprised if she hadn't seen them. Since I wrote them, many researchers have started to look more closely at our emerging understanding of hydrogen sulfide (including Kenny De Meirleir and Dr. Cheney) while others have reconsidered what has been know about overall sulfur metabolism in light of what we are now beginning to understand about H2S. Both approaches are all to the good, as I think this will lead to some answers for us.

I can't comment on Dr. Seneff's hypothesis on cholesterol sulfate, although I have said in the past that sulfur deficiency could be an answer for some people. I do know of one person who was cured of ME/CFS through sulfur supplementation.
The situation with ME/CFS sufferers is likely to be much more complicated. Between the many sulfur, glutamate and H2S-related allergies that people with CFS suffer from, the H2S-related anaerobic/aerobic gut imbalance (recently documented as leading to depression and anxiety), the CBS SNPs and the effect of such on the brain, and the sensitivity to environmental toxins that may interfere with sulfur and other gas metabolism at the mitochondrial level, it would be wonderful if we could find a clear and simple answer. In any case, I do think we are looking in the right place, and I hope that more and more people will focus their efforts in this area.

All best,
Marian