End ME/CFS Severe Patient Study Turns to the Mitochondria

[RuthAnn]

Okay, does anyone have their lactate dehydrogenase values? My enzyme values are consistently 60 to 70 per cent of normal. This enzyme quantity is under strict genetic control. Lack of LDH is one of the several glycogen storage disorders - number 11, I believe. Very little research.

LDH converts lactate to pyuvate and back, as well as NAD+ to NADH and back. The pyruvate is then chemically converted to several possible compounds, which then enter the citric acid cycle, where we get our big ATP production. When oxygen is in short supply, LDH converts pyruvate to lactate, with a small amount of energy production. Of course, this is a self limiting process, as lactate builds in tissues.

It is interesting that red blood cells have no mitochondria, and depend on LDH 1 ( these are 5 main isoenzymes for LDH) to convert pyuvate to to lactate, which yields some energy. The red blood cells use none of the oxygen they carry. Thus, could an LDH deficiency affect red blood cell activity ? No research on this that I have found.

So, LDH -1 is of critical importance to red blood cells and their activity. Mitochondria are not even involved.

Parvoviruses ( like B19 - which I have) can infect the precursor cells to mature red blood cells, and cause some anemia.

The biochemical apparatus is so complex that it takes research experts to address the possibilities.

@Merida does your LDH deficiency affect your large muscles (LDHA) or your heart(LDHB)?

I think I have seen some people develop rhabdomyolysis from taking statins. I am not suggesting that LDH deficiency is the same thing, but just very interesting that one can get the same problem through a different pathway. Statins affect the mevalonate pathway and affect production of heme, cholesterol, and one other thing that I can't remember. But I am now wondering if the LDH deficiency and statins both affect Complex IV through heme deficiency??

This is what it says about LDHA: "During the anaerobic phase of glycolysis (the Cori Cycle), the mutated enzyme is unable to convert pyruvate into lactate to produce the extra energy the cells need. Since this subunit has the highest concentration in the LDH enzymes found in the skeletal muscles (which are the primary muscles responsible for movement), high-intensity physical activity will lead to an insufficient amount of energy being produced during this anaerobic phase.[13] This in turn will cause the muscle tissue to weaken and eventually break down, a condition known as rhabdomyolysis."

 

[Snow Leopard]

The stress response systems don't know how to handle stuff so well anymore....

I spent some time reading all the neuroendocrine studies and my impression is that the HPA axis and adrenal glands are fine. My impression is that they are responding in a normal manner to issues caused elsewhere.

There does seem to be issues with the way the body handles stressors on the cellular level, with elevated oxidative stress, impaired HSP production and deficiencies in endogenous glutathione (and related) production... But this is of course quite different from what the average person or doctor means when they say stress. Stressful events might increase the risk through a whole host of reason - from diet/nutrient deficiencies, to over activity, to effects on the immune system (the spread of infectious disease also has social causes!). But it is neither necessary, nor sufficient to explain the persistence of the illness, hence I don't find it interesting enough to dig deeper along those lines.

The reason why there are studies consistently showing increased oxidative stress at the cellular level, we don't know, but perhaps it is a persistent defence mechanism against infection that persists through aberrant feedback loops? The hypotheses I have in mind have a little in common with Diabetes - but issues of lipid metabolism or lipid signalling in a different direction, either due to autoimmune causes, or metabolic & immune feedback loops in analogy with Diabetes.

 

[IrisRV]

IrisRv, we may be splitting hairs here, since we agree that stress sometimes may well be a contributing factor. Not speaking for anyone else, but that's all I've ever been saying.

This illness seems way too convoluted to point to any one factor as entirely causal. Even if one can establish a clear "triggering factor," that's not the same thing as a factor that's uniquely causal.

It appears that we agree on the basic points. I'm not arguing that stress cannot ever be a contributing factor. In fact, I imagine it is a contributing factor for a number of PWME.

But the flip side of that statement, in effect, sets you up as a gatekeeper of a disease notorious for its diverse manifestations and causes -- and difficulty to define. Paradoxically, it could make some people feel like you're telling them precisely what you most hate others telling you: that they're not really sick (at least not in the same category that you are).

It's clear I didn't explain myself as well as I should have. I do not believe that people who think that stress contributed to their illness, or even all those who believe stress caused their illness, do not have ME.

As humans, we have a hard time accepting that something this bad comes out of absolutely nowhere. We look for a 'cause'. When the cause is unknown, we examine our lives at the time our symptoms showed themselves for something different. We attribute our illness to that. The fact is, we're assuming a cause-effect relationship just because the two incidents happened at the same time. The two events could be entirely coincidental. Or they both could have been caused by a third effect we don't know about. We are simply guessing at cause -- all of us.

I don't think people who believe stress caused their illness necessarily don't have ME, but I do think they are not pointing to right cause if they do. By definition, physical symptoms caused by stress are psychosomatic. That's not my definition, or me drawing that line. Stress caused illnesses are psychosomatic illnesses, not ME. Illnesses caused by thyroid dysfunction are thyroid conditions, not ME. Illnesses caused by heart problems are cardiac illnesses, not ME.

If we don't draw lines somewhere, then everything is ME. That's nonsense. We can legitimately separate out things whose cause is already known. They are established illnesses in their own right.

This doesn't mean PWME cannot have those conditions. They're just not causal.

If it is a certainty that stress causes ME, as expressed above, then by definition the illness is psychosomatic. We can't pretend that's not true because we don't like the word. That's what psychosomatic is -- real physical symptoms caused by mental or emotional states.

Now I don't buy the whole psychosomatic hypothesis -- and it is only that, a hypothesis. It allows doctors to feel better about not knowing what's going on with an illness. It allows them to shift the responsibility from themselves to the victim. There is no hard evidence that stress alone causes serious illness. So I'm not buying that stress causes the serious neuroimmune illness ME. In my opinion, people who believe stress alone caused their ME are misattributing the cause, not that they don't have ME.

Again, by definition, an illness caused by stress is psychosomatic. Take your pick. If your serious illness is caused simply by your psychological state then it is psychosomatic. If it's caused by something not psychological, it's not psychosomatic. Unless you accept that ME is psychosomatic, you have to rule out stress as The Cause of ME. I don't buy that ME can be psychosomatic in some cases, yet biomedical in others. Ya gotta take your pick.

 

[IrisRV]

This is what it says about LDHA: "During the anaerobic phase of glycolysis (the Cori Cycle), the mutated enzyme is unable to convert pyruvate into lactate to produce the extra energy the cells need. Since this subunit has the highest concentration in the LDH enzymes found in the skeletal muscles (which are the primary muscles responsible for movement), high-intensity physical activity will lead to an insufficient amount of energy being produced during this anaerobic phase.[13] This in turn will cause the muscle tissue to weaken and eventually break down, a condition known as rhabdomyolysis."

Hasn't the Workwell and other exercise physiology research shown that anaerobic glycolysis is not failing -- that it's the aerobic glycolysis that's the problem? By the anaerobic failure theory, we should be fine doing everyday activities, but have trouble with activities that use anaerobic glycolysis such as long-distance running, when our HR is above 80-90% of our max. Don't we wish.

Correct me if I'm wrong, but I believe the research shows that we go from low level anaerobic (ATP-CP-phosphagen system) to the high level anaerobic (anaerobic glycolysis) unusually rapidly. Humans are designed to spend most of their time in the aerobic range. We don't. We go to anaerobic glycolysis doing everyday activities and our bodies naturally complain. It's like making our body sprint full out all day.

Both anaerobic systems appear intact, but anaerobic glycolysis produces lactic acid and goodness knows what other nasties than can't be cleared fast enough if we operate using anaerobic glycolysis routinely. Not a place to be living constantly.

That's why we are encouraged to exercise in <2 minute sets with rest -- that's about how long the low level anaerobic metabolism works before it needs to replenish. Fortunately, it replenishes fairly quickly. We're trying to train our low level anaerobic metabolism to carry more of the load so we can do more before dashing through aerobic metabolism ridiculously quickly and hitting anaerobic glycolysis. AT is your heart rate at that switch, aerobic glycolysis to anaerobic glycolysis. Typically, our AT is low -- meaning we switch to anaerobic glycolysis sooner than we should because our aerobic metabolism can't keep up.

This supports a mitochondrial dysfunction hypothesis for ME. Aerobic respiration is done mostly in the mitochondria, while anaerobic respiration is done mostly outside the mitochondria. So, if our mitochondria are too few or poorly functioning, they can't produce much energy by aerobic metabolism. As a result, we're forced to use anaerobic metabolism. All consistent with exercise studies... and many of our symptoms.

 

[RuthAnn]

@IrisRV , I can't reply to your post because I'm afraid I don't completely understand your point. All I can say is the information that I copied and pasted was meant for Merida who definitely has a lactate dehydrogenase deficiency. So while that information might apply to her, if she has the deficiency of the lactate dehydrogenase that affects the muscles, I am not implying that it would affect all with ME/CFS.

However, if ME/CFS is usually shown to have impaired aerobic function someone who also has impaired anaerobic function due to LHD deficiency would have extreme energy deficiency...if I'm understanding this correctly.

 

[RuthAnn]

It will be interesting to see what type of information comes out of the studies on mitochondria with respect to ME/CFS, but in the meantime, here's another angle for possible mitochondrial misfunction...ER stress.

http://www.ncbi.nlm.nih.gov/pubmed/22064245

Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics.

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER-mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders.

And EBV's involvement in endoplasmic reticulum stress and mitochondrial calcium homeostasis:

http://www.ncbi.nlm.nih.gov/pubmed/19650915

Modulation of B-cell endoplasmic reticulum calcium homeostasis by Epstein-Barr virus latent membrane protein-1

Because Epstein-Barr virus (EBV) can immortalize B cells and contributes to lymphomagenesis, in this work the effects of the virus on SERCA-type calcium pump expression and calcium accumulation in the endoplasmic reticulum of B cells was investigated.

 

[Paw]

This supports a mitochondrial dysfunction hypothesis for ME. Aerobic respiration is done mostly in the mitochondria, while anaerobic respiration is done mostly outside the mitochondria. So, if our mitochondria are too few or poorly functioning, they can't produce much energy by aerobic metabolism. As a result, we're forced to use anaerobic metabolism. All consistent with exercise studies... and many of our symptoms

Sounds plausible. And, perhaps, there are various other factors that can screw up the Cori cycle, causing a range of possible symptoms?

This is an area where we may some day pinpoint overlapping malfunctions of ME and FM, no?

It appears that we agree on the basic points. I'm not arguing that stress cannot ever be a contributing factor. In fact, I imagine it is a contributing factor for a number of PWME.

Thanks for your clarifying response to my earlier post. Makes sense. I think on the substance (which you're much more knowledgeable about) we don't disagree. Just rhetorically I might tend to be swayed more by how much we don't know. It's easier to name conditions that are clearly not ME, than it is to name exactly what ME is. As you say, even the term "psychosomatic" is just a convenient term -- often used to classify things we don't yet understand.

 

[Merida]

Judging from the results I am having from consistently taking biotin, I am thinking I must have something wrong with biotinidase function.

Biotin is important for heme production in Complex , and if heme isn't produced it causes a severe problem in Complex IV.

http://www.ncbi.nlm.nih.gov/pubmed/17182796

BD caused heme deficiency; there was a decrease in heme content and heme synthesis, and biotin-deficient cells selectively lost mitochondrial complex IV, which contains heme-a. Loss of complex IV, which is part of the electron transport chain, triggered oxidant release and oxidative damage, hallmarks of heme deficiency. Restoring biotin to the biotin-deficient medium prevented the above changes.

Besides causing heme deficiency, one would see a build up of iron.

"Heme, the major functional form of iron, is synthesized in the mitochondria. Although disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation, all of which are hallmarks of ageing, heme has been little studied in nutritional deficiency, in ageing, or age-related disorders such as Alzheimer's disease (AD)"

I think this might set one up for chronic lung infections, as at least two pathogens that I know of replicate on iron.

Also, "Moreover, biotin-deficient cells exhibited an increased susceptibility to oxidative damage in response to stress."

Yes, and disturbed heme production produces porphyrins - ie a known disease called porphyria. I have had conversation with a known porphyria patient. We are just like them. Lots of neuro issues, pain, fog, etc. Heme production ( in mitochondria?) uses a lot of ATP. So, under oxidative stress, more porphyrins are 'thrown off.'

Interesting: in The Fibromyalgia Syndrome ( edited by I Jon Russell, MD, PhD) , page 58, "FMS patients have exhibited marked morphological abnormalities in the red blood cells. These changes in shape of the RBC tend to make them less flexible thereby impairing their ability to enter the capillary bed. The loss of flexibility may reduce the blood flow and thus the delivery rate of oxygen and metabolic nutrients into tissue and also,inhibit the ability to dispose of metabolic waste." The original research on this was published by LO Simpson, " Nondiscocytic erythrocytes in myalgic encephalomyelitis. N Z Med J 102 (864): 126-127, 1989.

I have mentioned before that at one group meeting of about 15-17 women, 55 per cent of us were RH D neg. so, we lack the usual proteins on the red blood cell surface. These RhD proteins are thought to help get CO 2 out of the red blood cell.

I would like to repost all of this under the correct discussion, but can't find it ?? Nevertheless, red blood cells, their ability to produce their own energy ( via LDH pathways) and their ability to deliver O2 to cell mitochondria is a critical and interconnected phenomenon.

Plus, the shape of red blood cells is influenced by the osmotic concentration of solutes in the blood( ie NaCl). The Ph of the blood is highly regulated, and even minute changes cause serious problems.

Bottom line ( in my brain): This red blood cell issue is an important topic that needs thorough investigation. I have no idea how my deficient enzyme ( L DH) affects all of this. And I couldn't find anyone to answer the question. But, am going to try to find that researcher I mentioned.

Sorry to go on so long.

 

[Merida]

@RuthAnn
Thanks for the virus info. Yes, most of us were fine prior to viral infection/injury/ etc. So, something changed a basic process in our bodies that had been working fine? I have spent 18 years and thousands of $$$ trying to track it down. So, that is why I have pretty much turned to the Masters of wisdom ( ie QiGong/ shamanism/ mind-body/ great acupuncturist) to solve this. Just don't know the outcome yet.

 

[Seasprit]

Yes! Finally major researchers are following up on energy production issues instead of 'fatigue'! I'd guess that many of us have been thinking mitochondria for a long time. While we may have different hypotheses about the cause or trigger for mitochondrial dysfunction (viral, stress, autoimmune, toxin exposure), most of us understand that what makes us different is something to do with energy production -- which points straight to mitochondria.

We've had trouble getting mitochonrial experts involved because so far all known mitochondrial disorders are genetic diseases we don't have. Of course that doesn't mean we don't have an as-yet-unknown genetic disorder, or (more likely) an acquired mitochondrial disorder -- something that is entirely unknown at this point. If we hadn't been slapped with the psychosomatic label and the misleading and trivializing name CFS, major mitochondrial experts might have become interested in us much sooner.

For me, this is the most encouraging news we've had so far.

 

[Seasprit]

Open Medicine Foundation Study

The mantra at the Severely Ill/Big Data study at the Open Medicine Foundation is to follow the evidence where it leads. We don't know exactly what Davis has found or if will be ultimately validated. We do know that something eyebrow raising involving the mitochondria has shown up in the early stages of the Open Medicine Foundation's End ME/CFS Severely Ill study. Something eyebrow raising enough for a mitochondrial expert to join the fold.

[fright]View attachment 1164 [/fright]Davis has found abnormalities before but this is the first one, he told me, that has really leapt off the charts. It was orders of magnitude different from normal.

Whatever the finding is it has apparently lead to a mitochondrial expert, Robert Naviaux, MD, PhD being added to the Open Medicine Foundation's Scientific Advisory Board.

We've had mitochondrial findings before but not from researchers of his ilk. Naviaux is not a doctor and sometime researcher. He's a full-time mitochondrial researcher. His first paper on the subject occurred about 15 years ago. Since then he's co-authored more than 80 studies on the mitochondria, genetics, metabolism and metabolomics. The metabolomics study that highlighted the possible mitochondrial issue in ME/CFS has been submitted to the Journal of the American Medical Association (JAMA). Publication, if it comes, is hoped for in early spring/summer.

[fleft]View attachment 1163 [/fleft]He runs the Robert Naviaux Laboratory at UC San Diego, and is the founder and co-director of the Mitochondrial and Metabolic Disease Center at UCSD.. He's also the co-founder and a former president of the Mitochondrial Medicine Society, and a founding associate editor of the journal Mitochondrion. This man is steeped in the mitochondria - but he also has an interesting immune side.

Naviaux trained at the NIH in tumor immunology and natural killer cell biology, and at the Salk Institute in virology and gene therapy. With all that experience he seems perfectly placed to understand the role infection/inflammation may play on mitochondrial issues, should they continue to show up, in ME/CFS. In conversation Ron Davis has suggested that mitochondrial problems with the immune cells could conceivably be driving the immune dysfunction in ME/CFS.

A busy researcher in a hot field, his joining of the OMF Scientific Advisory board speaks volumes about the possible significance of Davis's recent finding. Naviaux wouldn't sign on if something very intriguing hadn't sparked his interest. One patient reported Naviaux replied to her email.



Davis has stated that Dr. Nath of the NIH's Clinical Center study has been informed of what they've found.

The Chronic Fatigue Initiative's Mitochondrial Emphasis

J Transl Med. 2016 Jan 20;14(1):19. doi: 10.1186/s12967-016-0771-6.Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome.
Billing-Ross P1, Germain A2, Ye K3, Keinan A4, Gu Z5, Hanson MR6.

The Chronic Fatigue Initiative's move to the mitochondria recently resulted in a paper published by Maureen Hanson of Cornell University. The study involved sequencing the entire mitochondrial genome of almost 400 ME/CFS patients from five sites across the U.S. It determined whether single or groups of variations in mitochondrial genes or something called heteroplasmy were more common in ME/CFS.

The study found no evidence of inherited genetic disease or heteroplasmy in ME/CFS but one finding suggested that people whose genome gives them an increased tolerance of oxidative stress may be at reduced risk of coming down with ME/CFS. (The mitochondria produce large numbers of free radicals). ME/CFS patients with a group of variations in some mitochondrial genes also tended to display more joint pain, bloating, chemical or light sensitivity, disrupted sleep and experience more dead/heavy feelings after exercise.

This study did not suggest that variations in the mitochondrial genome caused ME/CFS but it did suggest that once you have ME/CFS some mitochondrial variations might make it worse. That could suggest that something affecting mitochondrial functioning could be present in ME/CFS.

One study that found evidence of mitochondrial genetic issues in ME/CFS and other "functional disorders" concluded that the "pathophysiology likely involves broad effects on the autonomic nervous system."

There's the genetics of mitochondrial disease and then there's mitochondrial functioning. If an autoimmune or some other process is affecting the mitochondria then genetic problems need not be present for a disease to have a mitochondrial basis. The next step for Maureen Hanson and the CFI is to determine if mitochondrial problems caused by an autoimmune or another process are impairing the functioning of immune cells in ME/CFS.

Conclusion

The mitochondria are finally getting some serious attention in ME/CFS. Mitochondrial problems have been found before in the disease and interest is growing in the subject. Newton recently showed for the first time that mitochondrial disorders can cause fatigue as severe as that found in ME/CFS. She found comparable levels of fatigue in about a third of people with mitochondrial disorders. She suggested that future treatments developed to assist mitochondrial patients may be able to help people with ME/CFS. With results like that and researchers like Naviaux and Hanson in the mix, mitochondrial issues should be getting more attention in ME/CFS.

Cort, I wonder if there is (or could be) a scientific Foundation where people with DX of Fibromyalgia etc. could donate tissue samples (after surgeries/death) that could be studied for any links to the mitochondria or other research looking at causal factors??

 

[Merida]

@Seasprit
Yes, check out this site : solvecfs.org/biobank

 

[Cort]

One more interesting story: One year ago I went to South El Monte, CA to have a session with Grandmaster Zhou - " the Jewel of China" , " the Healer's Healer." He speaks no English, so there was an interpreter. He did a one hour ' qi gong' massage. Was very serious.

After the session I asked ( through interpreter), " why have I been sick for so long, and have so many symptoms? "
He smiled and said, " You are a kind and generous person. You gave away your energy." I was completely floored.

I then asked, "What can I do to get better and stay well? " He said, " Try to breathe."

I actually agree. I don't think until this last year that I've taken a really deep breath in thirty years. My breathing is just messed up.

 

[Paw]

I actually agree. I don't think until this last year that I've taken a really deep breath in thirty years. My breathing is just messed up.

Amen to that. I can't tell you how often I'm awakened from a nap because I'm not taking in a breath, or just breathing very shallowly. But my apneas from physical restrictions are very mild.

Meanwhile, Merida's note about inflexible red blood cells causing oxygen shortages makes me shake my head in wonderment at how complex and interwoven all this may be.

 

[Who Me?]

I've started using an inhaler (online pharmacy that sells glaxo smith kline) and it seems to really be helping my breathing. Not only can I breath better but I feel like my brain is a bit clearer.

The real difference came after a few months of abx to knock back my mycoplasma pneumonia.

 

[Zapped]

My problems breathing are worst when I exercise while breathing into a large balloon -
I seem to just go to sleep... ... Must be stress .

...April fools!

 

[Rosie26]

I actually agree. I don't think until this last year that I've taken a really deep breath in thirty years. My breathing is just messed up.

My breathing isn't right either. I've tried to take longer and deeper breaths but I always automatically fall back into the shallow faster intakes. And then sometimes I realize I have stopped breathing and have to quickly gasp in some air. That doesn't happen often just every now and again. It's been about 20 years for me, I think.

 

[Cort]

It will be interesting to see what type of information comes out of the studies on mitochondria with respect to ME/CFS, but in the meantime, here's another angle for possible mitochondrial misfunction...ER stress.

http://www.ncbi.nlm.nih.gov/pubmed/22064245

Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics.

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER-mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders.

And EBV's involvement in endoplasmic reticulum stress and mitochondrial calcium homeostasis:

http://www.ncbi.nlm.nih.gov/pubmed/19650915

Modulation of B-cell endoplasmic reticulum calcium homeostasis by Epstein-Barr virus latent membrane protein-1

Because Epstein-Barr virus (EBV) can immortalize B cells and contributes to lymphomagenesis, in this work the effects of the virus on SERCA-type calcium pump expression and calcium accumulation in the endoplasmic reticulum of B cells was investigated.

Another possibility= thanks for posting that I had heard of ER stress before but didn't know what it was about.

 

[Cort]

Hasn't the Workwell and other exercise physiology research shown that anaerobic glycolysis is not failing -- that it's the aerobic glycolysis that's the problem? By the anaerobic failure theory, we should be fine doing everyday activities, but have trouble with activities that use anaerobic glycolysis such as long-distance running, when our HR is above 80-90% of our max. Don't we wish.

Correct me if I'm wrong, but I believe the research shows that we go from low level anaerobic (ATP-CP-phosphagen system) to the high level anaerobic (anaerobic glycolysis) unusually rapidly. Humans are designed to spend most of their time in the aerobic range. We don't. We go to anaerobic glycolysis doing everyday activities and our bodies naturally complain. It's like making our body sprint full out all day.

Both anaerobic systems appear intact, but anaerobic glycolysis produces lactic acid and goodness knows what other nasties than can't be cleared fast enough if we operate using anaerobic glycolysis routinely. Not a place to be living constantly.

That's why we are encouraged to exercise in <2 minute sets with rest -- that's about how long the low level anaerobic metabolism works before it needs to replenish. Fortunately, it replenishes fairly quickly. We're trying to train our low level anaerobic metabolism to carry more of the load so we can do more before dashing through aerobic metabolism ridiculously quickly and hitting anaerobic glycolysis. AT is your heart rate at that switch, aerobic glycolysis to anaerobic glycolysis. Typically, our AT is low -- meaning we switch to anaerobic glycolysis sooner than we should because our aerobic metabolism can't keep up.

This supports a mitochondrial dysfunction hypothesis for ME. Aerobic respiration is done mostly in the mitochondria, while anaerobic respiration is done mostly outside the mitochondria. So, if our mitochondria are too few or poorly functioning, they can't produce much energy by aerobic metabolism. As a result, we're forced to use anaerobic metabolism. All consistent with exercise studies... and many of our symptoms.

I think you are right. The anaerobic energy production system is just doing what it's doing although come to think of it Newton is finding problems with pH and lactate clearance..... Anyway it simply can't replace the aerobic energy system - which is where the main problem is in ME/CFS. That's my understanding, anyway.

 

[Snow Leopard]

Yes, a paper has been submitted to JAMA recently.

I wonder how that is going?