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Study Suggests "Bad Energy" is Core Problem in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)

  [ 42 votes ]   [ 1 Comment ]
By Cort Johnson • www.ProHealth.com • June 11, 2017


Study Suggests
Reprinted with the kind permission of Cort Johnson and Health Rising.
 
Lactate has become a big deal in both chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).  A by-product of anaerobic energy metabolism, lactate ordinarily gets pumped out of our cells in large amounts during exertion. The lactate findings suggest that the energy needs of ME/CFS/FM patients are largely being addressed by glycolysis or anaerobic energy production. Anaerobic energy production plays an important role in energy production, but when aerobic energy production is not available and it becomes the major source of energy, it produces metabolites that produce the burning muscles, fatigue and other symptoms we associate with over-exercise.
 
That makes it all the more shocking and puzzling to find high lactate levels in two diseases in which exercise is often hardly tolerated. That suggests that something is profoundly off with ME/CFS and possibly FM patients’ energy productions systems. The fact that increased lactate levels have been found in several different compartments of the body in these diseases only sharpens the interest.
 
We mostly focus on lactate in the muscles and blood, but high lactate levels have also been found in the brains of people with chronic fatigue syndrome (ME/CFS). Over the past ten years, Dr. Shungu and Dr. Natelson have documented large lactate increases in the ventricles in the brains of ME/CFS patients. They’ve also found large decreases in brain glutathione levels as well.  In their latest study, they went a step further and examined lactate levels in the brains of FM patients as well.
 
Ventricular Lactate and the Cerebrospinal Fluid
 
When Dr. Shungu and Dr. Natelson refer to ventricular lactate, they’re also referring to the cerebral spinal fluid – a “tissue” that is becoming increasingly important in ME/CFS and FM. The ventricles are four cavities sitting at the bottom of the brain where the cerebral spinal fluid (CSF) is produced. The CSF functions as a kind of cushion, a blood flow and neuro-endocrine-immune regulator and as an important waste removal outlet.
 
Analyzing the cerebral spinal fluid is the closest we can get to the brain, short of a biopsy. CSF studies are able to uncover several different kinds of pathologies associated with the brain including bleeding, infection, inflammation and autoimmunity. Protein analyses of CSF have identified unique protein signatures for multiple sclerosis, lupus and other diseases.
 
Cerebral spinal fluid studies are also beginning to unlock what’s going on in ME/CFS/FM. CSF studies from the Simmaron Research Foundation and the Center for Infection and Immunity uncovered a pattern of immune upregulation / exhaustion and identified an atypical ME/CFS subset.  Other CSF studies found a different protein signature in ME/CFS vs. Lyme disease and evidence of increased intracranial pressure in ME/CFS. Low levels of glutathione suggest the brain’s antioxidant defenses are down.
 
This study examined the makeup of CSF – aka the brain ventricles – in ME/CFS, FM, and healthy controls
 
The Study
 
Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia. Benjamin H. Natelsona, Diana Vua, Jeremy D. Coplanb, Xiangling Maoc, Michelle Blatea, Guoxin Kangc, Eli Sotod, Tolga Kapusuzd and Dikoma C. Shungu. FATIGUE: BIOMEDICINE, HEALTH & BEHAVIOR, 2017 http://dx.doi.org/10.1080/21641846.2017.1280114
 
Four studies have found increased lactate in fibromyalgia, and three studies have found it elevated in ME/CFS patients’ brains. This study used an H MRS I scan to examine lactate levels in 74 ME/CFS, ME/CFS + FM, FM and healthy controls’ brains.
 
It found highly increased levels of lactate in the brains of chronic fatigue syndrome (ME/CFS), fibromyalgia, and ME/CFS+FM patients.
This means increased lactate levels may be one of the few abnormal findings present in both ME/CFS and FM. In fact, the authors – two longtime ME/CFS/FM researchers – believe lactate elevations are likely to be a core part of both syndromes. Further study is needed, but this could be the tie that binds the two disorders together.
 
I asked the senior author of the study, Dr. Shungu, how he got interested in lactate and ME/CFS/FM in the first place.
 
It turned out that he got drawn into ME/CFS research in the most backdoor way impossible.  Fascinated by some brain scans he’d been asked to analyze that were suggestive of mitochondrial disease, he asked who they were from.  It was only then that he found out they had chronic fatigue syndrome (ME/CFS) and had come from Paul Cheney, MD. So began a decade-plus journey with ME/CFS – one which has yielded important insights. 

“As with many, if not most, scientific endeavors, it was serendipity, and it also intertwines with how I got started in this area of research. My interest in ME/CFS research first emerged out of nowhere in 2002 after I had the opportunity to conduct diagnostic (as opposed to research) brain MRI/MRS evaluations and “metabolic workup” in patients with ME/CFS, who turned out to be patients of Dr. Paul Cheney (I did not know who he was at time and I had never heard of ME/CFS).
 
The results of that fairly routine clinical brain MRI/MRS scan piqued my interest because – and here are the answers to your ‘how?’ and ‘why?’ questions above – they revealed elevations of ventricular lactate similar to those that we had observed in patients with primary mitochondrial disorders, which I was investigating at the time as a Radiology faculty member at Columbia University Medical Center.”

Those increased lactate levels are basically synonymous with mitochondrial dysfunction…
 
We have found elevated ventricular lactate in nearly every disorder in which mitochondrial dysfunction has been implicated. These include primary mitochondrial disorders that I am still investigating with researchers at Columbia [Kaufmann et al 2004, Weiduschat et al 2014], Parkinson’s disease, lysosomal storage diseases, etc.  We also recently reported increased ventricular lactate in FM, as well.
 
Shungu’s next steps revealed just how important small pilot studies funded by organizations like the Solve ME/CFS Initiative (SMCI), the Open Medicine Foundation and the Simmaron Research Foundation can be. Three seed grants from the SMCI kept his work going.
 
Greatly intrigued, I decided to find out more about ME/CFS, and I then teamed up, first with Dr. Susan Levine, and then with Dr. Benjamin Natelson, to apply (successfully) for three successive “seed” grants from the CFIDS Association of America (now Solve ME/CFS Initiative) to investigate, using brain MRI/MRS, whether mitochondrial dysfunction was responsible for the elevations of ventricular lactate that we’d observed in ME/CFS [Mathew et al 2009, Murrough et al 2010, Shungu et al 2012].
 
Shungu was then able to turn the pilot data gained into grants totaling almost $2 million. That’s a great return on investment for people who donated to the cause. That return on investment continues to build: Shungu has produced a comprehensive hypothesis on how ME/CFS begins and is maintained, and is submitting further grant proposals.
 
With these preliminary data and new evidence, which consisted of a robust 36% deficit of cortical glutathione (GSH) – the most abundant and primary antioxidant in living tissue – in ME/CFS compared to controls, we competed for NIH funding and were awarded two grants, descriptively titled, “Specificity and Validity of Oxidative Stress Model of Chronic Fatigue Syndrome” (R01 MH100005) and “[N-acetylcysteine] NAC for Treatment of Oxidative Stress in Chronic Fatigue Syndrome” (R21 NR013650). 
 
Oxidative Stress
 
Even though it was the similarity between mitochondrial disorders and ME/CFS that initially spurred his interest, Shungu has come to conclude that the primary problem in ME/CFS involves oxidative stress and that mitochondrial problems are secondary. 

Rather than directly implicating mitochondrial dysfunction, the three studies culminated with strong evidence supporting oxidative stress and associated pathophysiological consequences as the most likely neurobiological underpinnings of the observed elevations of ventricular lactate in ME/CFS [Shungu et al 2012].

Shungu’s last NIH funded (2013-2017) grant examined oxidative stress levels in the blood, urine and cerebral spinal fluid and determined if increased levels were synonymous with increased symptoms and reduced functionality. That study is finished and its results buttressed Shungu’s view that oxidative stress is a major component of ME/CFS/FM. 

Both studies have now been completed and they have solidified our view that oxidative stress is a major player in ME/CFS etiopathogenesis. Shungu

Why does Shungu believe mitochondria dysfunction is probably secondary in ME/CFS? Because he’s not seeing alterations in the levels of brain ATP and other phosphates or reduced levels of NAA.  The one proviso is that he’s been studying patients at rest. Next he plans to combine an exercise challenge with an MRS brain scan to determine if energy replenishment is occurring normally. Only then will he know for sure if the mitochondrial problems are primary or secondary.
 
For now, Shungu is focusing heavily on an oxidative stress model. High levels of free radicals that can chew up and blast cells – and even affect blood vessel functioning – have been found several times in ME/CFS and FM.
 
Oxidative stress itself is a normal part of cellular functioning. During the process of aerobic energy production, the mitochondria produce enormous amounts of free radicals, and immune cells use free radicals to kill pathogens as well. Too much oxidative stress, however, can damage the mitochondria and impair cellular functioning. Shungu’s finding of highly reduced levels of glutathione in the brains of ME/CFS patients suggested that the antioxidant systems that normally keep oxidative stress in the brain in check were not doing so any more.
 
High levels of isoprostanes in two (ME/CFS) studies, including one of Shungu’s (unpublished), provided an important early clue for Shungu. Isoprostanes are turning out to be major players in both cardiovascular and neurological diseases.
 
Shungu’s model – which builds on Martin Pall’s ME/CFS NO/ONOO model –  goes something like this: 
  • An immunological trigger or pathogen triggers the production of pro-inflammatory cytokines and the potent free radical peroxynitrite.

  • Inadequate antioxidant reserves result in peroxynitrite reacting with lipids to form isoprostanes.

  • Isoprostanes – potent vasoconstrictors – compress the blood vessels, reducing blood flow, and producing an hypoxic or low oxygen environment.

  • That low oxygen environment: (a) results in increased anaerobic energy production (glycolysis); and (b) promotes the transformation of pyruvate into lactate – hence, the high lactate levels found in the brain. 

Shungu believes mitochondrial dysfunction is present in ME/CFS; he just doesn’t believe it’s the driver of the disease.
 
I believe that mitochondrial dysfunction is present in ME/CFS. It’s just that it is not a driver of the disease (i.e., not pathogenic), and it is fairly mild under resting conditions. The way mitochondrial dysfunction likely becomes more manifest in ME/CFS is when symptoms are provoked and de novo energy production is required…
 
It’s not that the mitochondria are not involved – they are – but they’re not getting whacked by a problem that they have. They’re getting whacked by the neuroinflammation and oxidative stress that’s present. The general outlines of Shungu’s model don’t appear to be that far from Naviaux’s, Davis’s and Fluge and Mella’s models that something in the blood is turning off the mitochondria in the cells, and according to Shungu and Fluge/Mella is also affecting the blood vessels and blood flows. Again, that something for Shungu, is oxidative stress and neuroninflammation.
 
“… mitochondria are incapacitated by the primary lesions (oxidative stress, neuroinflammation) in the disorder, leading to ineffective replenishment of cellular energy. Shungu
 
Once the process starts, it can be hard to tell what is causing what as the mitochondrial and oxidative stress problems feed into each other:
 
In our study of primary mitochondrial disorders (e.g., MELAS), we have found a cortical GSH deficit that seems to be even bigger than in ME/CFS, meaning that mitochondrial dysfunction and oxidative stress co-exist and likely potentiate and sustain each other in such disorders.
 
Fibromyalgia – A Neuroinflammation Disorder?
 
At least three possible mechanisms could explain the increased lactate levels seen in FM: problems with anaerobic energy production / mitochondrial dysfunction, neuroinflammation and oxidative stress. Again, note that none of them are exclusive of each other. Oxidative stress can whack the mitochondria and cause neuroinflammation.
 
Neuroinflammation, on the other hand, is a really potent oxidative stress inducer. The question is where does it all begin?
 
Right now, Shungu’s betting on the neuroinflammation option for fibromyalgia, but believes oxidative stress, neuroinflammation and mitochondrial dysfunction are all “co-conspirators” in producing ME/CFS, FM and other diseases.
 
I think that you are right in suggesting that pain and increased ventricular lactate in FM may have a different mechanistic underpinning (than in ME/CFS) and a strong candidate is neuroinflammation.
 
Personally, and this is the next phase of our research, I believe that oxidative stress and neuroinflammation, and possibly a secondary mitochondrial dysfunction, may all be ‘co-conspirators’ in the etiology of most of these unexplained and highly overlapping and related multisystem /multisymptom diseases like ME/CFS, FM, Gulf War, IBS, etc.
 
One of his earlier studies found that Savella (milnacipran) significantly reduced FM patients’ pain as well as their ventricular lactate levels. Despite those reductions, the FM patients’ lactate and pain levels were still higher than in the healthy controls. That suggested that further reductions in ventricular lactate levels might be able to reduce pain levels even more. I asked him about that.
 
It was clear that Savella can only go so far in FM. Might other drugs or classes of drugs or other substances do better in reducing brain lactate levels? He suggested that it wasn’t going to be as easy as that. 
 
This suggests that a single drug that targets ventricular lactate may not be effective because it would be targeting a consequence rather than the cause of the disease. This also suggests that a ‘drug cocktail’ that targets the complex etiologic factors of these disorders may be more effective than a single drug. Thus, combining N-acetylcysteine (NAC) to elevate brain glutathione levels and alleviate oxidative stress, with, e.g., a non-steroid anti-inflammatory drug (NSAID) to target inflammation might be more effective than either intervention alone.
 
(Dr. Shungu’s NAC trial had positive results. We are awaiting publication.)
 
As for a drug that might be more effective at reducing lactate, we did conduct a clinical trial of precisely such a drug – dichloroacetate or DCA –  in patients with the syndrome of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS), a primary mitochondrial disorder with gallons of ventricular lactate. However, we had to abort the trial because we found DCA to induce toxic neuropathy in MELAS patients [Kaufmann et al 2006]. Perhaps DCA would be safer in patients with milder lactate elevations, which ME/CFS and FM have in comparison to MELAS.
 
While Shungu is pointing at a different or at least an additional cause of the high lactate levels he’s found, it’s important to note that the same endpoint has shown up again and again:
 
With regards to the single syndrome hypothesis: could the general finding of increased lactate in the ventricles of ME/CFS and FM point to a similar neuroinflammatory state in ME/CFS and FM which is expressed slightly differently – producing more fatigue in one disease and more pain in the other?
 
We have done so little research in neuroinflammation and the data on it in ME/CFS or FM is so discrepant that it is tough to speculate. So, I will have to ask you to stay tuned, because we now have a proposal pending to combine MRS with positron emission tomography (PET), the “gold standard” approach for measuring neuroinflammation, to extend our oxidative stress model of ME/CFS (also applicable to related multi-symptom disorders) upstream to try to obtain empirical evidence supporting neuroinflammation as the “missing mechanistic link” between oxidative stress and ME/CFS etiopathogenic factors like systemic immune dysfunction.
 
Conclusion
 
The most important takeaway from this study and from Shungu’s and Natelson’s work is that the same central finding – an overemphasis on anaerobic energy production – is showing up in both ME/CFS and FM, and it appears to be showing up across the body.
 
What’s causing the problem is almost secondary at this point. The biggest issue in ME/CFS research has been identifying the core problem present. If it’s true that problems with energy production are that core issue, then what’s left is the working out of why and how it showed up and how to fix it. That’s a much easier task than finding the core problem and one that the NIH and others should find much easier to fund.

About the Author: ProHealth is pleased to share information from Cort Johnson.  Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.



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Article Comments Post a Comment

Pyruvate
Posted by: JoeSiebert
Jun 11, 2017
I wonder if there is any connection between the notion that the condition promotes the transformation of pyruvate into lactate and Ron Davis's finding that adding pyruvate to the serum in his assay makes ME/CFS cells look healthy again. Definitely seems like there is some real overlap beginning to emerge in the findings of top researchers.

Thanks for your tireless efforts to keep us all updated, Cort!
Reply Reply
 
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