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The long presentations featured in Emerge;s recent conference allowed some researchers to really dig into their topics

The long presentations featured in Emerge’s recent conference allowed some researchers like Neil McGregor to really dig into their topics.

This is the first in a series of blogs that report on the recent EMERGE conference in Australia. The different conference format – which allowed for long presentations – allowed the presenters to dig more deeply into their topics than usual. Longtime Australian metabolomics researcher Neil McGregor took full advantage of this opportunity to give his grand conception of what’s going on with chronic fatigue syndrome (ME/CFS).

Neil McGregor reported that Ron Davis challenged members of his Working Group (of which McGregor has been a part) to develop a hypothesis.  It’s rare in my experience – quite rare – that: a) researchers are challenged to do this; and b) they accept the challenge and then publicly present it.

Most conference presentations consist simply of presenting data from a study.  Sometimes researchers even feel the need to inform the audience what ME/CFS is.  (Why, why, why?) Much of the talk is then filled with methodology and, their fifteen minutes in the public eye almost up, they squeeze in their results at the end, then leave the platform – the implications of their findings unstated.

Too rarely does anyone climb out onto the skinny branches and say, this is MY conception – my grand idea of what ME/CFS is. At the EMERGE conference in Australia, Neil McGregor did just that. Not only did he attempt to tie everything together that he could but it made for a very interesting presentation.

He started off with a rather astounding assertion – that he’s able to separate infectious from gradual onset patients using metabolites. To be able to show, years after onset, that some fundamental differences persist in these two groups would be a significant breakthrough. Not only would it suggest that gradual and infectious onset patients are different, but the metabolites should, of course, tell us how these two symptomatically very similar presentations of ME/CFS are different biologically.

Out onto the skinny branches Neil McGregor went as he presented his grand idea of what has happened in ME/CFS

Out onto the skinny branches Neil McGregor went as he presented his grand conception of what’s gone wrong in ME/CFS.

Then, if I got it right, McGregor also showed that an ME/CFS patient’s metabolites could show whether that person had exercised recently and had post-exertional malaise (PEM) using their metabolites.  Those metabolites – which are breakdown products –  should point an arrow at where the breakdown during exercise occurred.

It should be noted that metabolomics is a bit twitchy! Metabolites, McGregor pointed out, can be altered by any number of factors (diet, exercise, drugs). A metabolites expert spent most of his talk at the recent NIH ME/CFS Conference explaining how the field was making up for its shortcomings.

The Study

McGregor’s study collected first morning urine – when many patients are at their worst – and then blood when patients found their way to the clinic.  That was done in order to remove as many confounding factors as possible (metabolites can be affected by many factors).

McGregor found that fasting morning glucose levels increased and lactate decreased with increasing PEM.  (Yes, lactate decreased!)

(Rebound Hypoglycemia or the “Dawn Effect” in ME/CFS – Higher than normal levels of morning glucose can reflect either something called the Somogyi effect or “rebound hyperglycemia” in diabetics or the “dawn effect” in non-diabetics.

 

Rebound hyperglycemia in the morning occurs when your blood sugar drops too low during the night, In order to “rescue” you from the dangerously low blood sugar levels, hormones are released which tell your liver to dump glucose into your bloodstream. Not too surprisingly, the low glucose levels can play havoc with your sleep, causing nightmares, restless sleep and night sweats. Rebound hyperglycemia is diagnosed by measuring glucose levels around 3 AM.

 

The “dawn effect”: many people’s glucose levels rise early in the morning. If glucose levels are higher than normal upon wakening, but normal around 3 AM, the dawn effect is occurring.

McGregor’s findings suggested, once again, that glycolysis – that very early step in the process of producing energy – is off kilter in ME/CFS.  As glucose is converted to pyruvate (a fairly simple process 🙂 – see diagram), some ATP and a compound called NADH are produced.

Glycolysis – Just another simple pathway… (from Wikimedia: https://en.wikipedia.org/wiki/File:Glycolysis_metabolic_pathway_3_annotated.svg)

All this activity, it should be noted, is taking place in the anaerobic cytoplasm of the cell – not in the mitochondria. Note also that 10 enzymes are involved in glycolysis – providing plenty of opportunity for something to go wrong.

Pyruvate then moves into the mitochondria where things really get rolling, but note that without that pyruvate – if something has gone wrong with glycolysis – nothing happens.

The Last Worst Option

The higher levels of hypoxanthine – a breakdown product of ATP – suggested to McGregor that the ATP in people with ME/CFS  was being broken down at a higher rate than normal – leaving less ATP available.

The news was worse than that, though.  Our cells want to use glucose to produce energy; if they can’t get glucose they’ll turn to fats – not such a bad substitute, but if the fats aren’t working, they’re forced to turn to their last and least favorite option – breaking down proteins.

exhaustion after exercise in ME/CFS

McGregor believes the muscles are being broken down to provide energy in ME/CFS.

The hypoxanthine levels suggested that’s what was happening in ME/CFS, and the urine and blood amino acid tests bore that out. High levels of muscle metabolites suggested that whatever muscles the people with ME/CFS had left were being broken down faster than normal.

Breaking down the muscles of an exercise intolerant, muscle depleted group of people seemed like a rather strange (and cruel) thing to do, but there was a good reason for it.  If the body places a premium on any process, it would be energy production. The great majority of energy we use, after all, goes not to exercise or digestion but to simply keeping our body going.

Given that rather essential need, our bodies will apparently do just about anything – including breaking down our muscles – to keep a broken energy production cycle going.

If that’s what’s going on in ME/CFS, we are not alone; McGregor reported that this kind of hyper-catabolic, hypermetabolic response is also seen in burns, post-surgery and sepsis states. McGregor suggests ME/CFS patients have been shifted into an abnormal metabolic state.

Both burn and ME/CFS patients show loss of amino acids, insulin resistance, connective tissue degradation (an interesting finding given the EDS and craniocervical instability problems), altered triglycerides, cortisol, a switch from ATP production to “thermogenic” response, and gut-barrier issues. (Ron Davis, by the way, is finding high levels of connective tissue metabolites in the severely ill patient group he’s studying. Those metabolites could suggest that increased connective tissue degradation is occurring.)

McGregor, then, believes that problems with glucose metabolism are at the core of what is happening in ME/CFS.

The Glucose Tolerance Test Results

McGregor then turned to a HUGE sample size (n=777) of ME/CFS glucose tolerance test results.

In a glucose tolerance test (GTT), glucose is consumed and blood samples are taken afterwards to determine how quickly glucose is cleared from the blood.  GTT’s are usually used to test for diseases and conditions like diabetes, insulin resistance, impaired beta cell function, and reactive hypoglycemia.

Glucose tolerance test abnormalities in ME/CFS

Glucose tolerance test abnormalities in ME/CFS: normal – green, truncated – blue, flat – purple.

Three types of responses show up in ME/CFS.  A small group of patients had a normal result (10%), most had a truncated (82%) glucose response, and a small group had a flat (7%) response.

For most, the peak in glucose occurred quickly (30 minutes) after which, as McGregor put it, their glucose levels traveled south (diminished) at a rapid rate. In fact, they traveled south so quickly that almost 30% of the group was hypoglycemic (low glucose levels) by 60 minutes and many others would most likely have been hypoglycemic shortly after that. Glucose did not hang around long in McGregor’s ME/CFS group.

Glucose Tolerance Testing Plus Metabolomic Equals…

McGregor then tied together the GTT results with metabolomics results to see if abnormal metabolic breakdown products were correlated with the altered glucose uptakes.

Flat response (10%) – The metabolite results suggested that the people in this group had very low creatinine levels, and that an autoimmune response was likely occurring.

Truncated Response (82%) – People with the more common truncated response had low urea (low nitrogen) and very low creatinine levels. Because creatinine is an important factor in the production of energy in the muscle, brain and cardiac tissue, the low creatinine levels translated into low energy levels.

As noted earlier, inhibited glycolysis results in an increase in ATP breakdown. Since problems with glycolysis cause the body to scavenge creatinine from the muscles for energy, the low creatinine levels made sense.

Exercise causes a similar result in healthy people, but their creatinine levels get replenished within hours. The low creatinine levels found in this ME/CFS group suggested that their muscles are not getting replenished, even with the pitiful amounts of activity they can generally engage in.

The two-day exercise tests pioneered by the Workwell group suggest something like this must be happening. Some part of the energy production process must be depleted or damaged or interfered with for a short exercise period one day to be able to impair exercise the next day.

Nancy Klimas’s exercise and mega testing regimen suggests exercise is immediately sparking an intense burst of inflammation in ME/CFS, which then goes on to whack the autonomic nervous system, hormones, antioxidant system, etc. McGregor’s findings suggest that depleted muscles may be part of the package as well. If McGregor is right, hopefully that depletion will show up in Nath’s and Tompkins’s muscle biopsy work.

depletion mcgregor ME/CFS

McGregor’s results suggest the muscles and other tissues are being depleted of vital metabolites.

McGregor’s results suggest that people with ME/CFS are in a hypermetabolic (not hypometabolic) state – a state in which the body is pulling out all its stops in an attempt to get energy. (McGregor’s hypermetabolic idea seems to fit with the sympathetic nervous system activation/parasympathetic nervous system inhibition going on in ME/CFS.)

One of the consequences of a hypermetabolic state is, not surprisingly, an elevated heart rate. McGregor found that the metabolites elevated in people with greatest increase in HR upon standing were, indeed, consistent with a hypermetabolic and hypercatabolic (muscle breakdown) state.

McGregor found that the more post-exertional malaise (PEM) a person experienced, the more metabolite dumping (and hence more muscle catabolism or breakdown) was present as well.

That process, unfortunately, puts ME/CFS patients into one of nature’s catch-22s. Breaking muscles down to produce energy causes a raft of metabolites to get dumped into the urine. These are the same metabolites, though, that we need to replenish in our muscles. Some energy, then, is being produced, but at a longterm cost to the muscles.

This dumping/amino acid depletion is, McGregor believes, a key issue in ME/CFS. It can help explain why ATP production is low and why the disease is so darn difficult to get out of. Until the problem with glycolysis is resolved and ME/CFS patients’ cells can get back to primarily using glucose and fats to produce energy, their proteins – and that means their muscles and other tissues, are going to keep getting broken down.

That, McGregor believes, results in problems not just with the muscles but with gut malabsorption, connective tissue issues, difficulty fighting off infections, inflammation, heavy metal absorption, etc.

Gut barrier problems (e.g. leaky gut), for instance, are common in hypermetabolic states. McGregor noted that Shukla showed that exercise – which is simply going to exacerbate the amino acid depletion – results in the gut leaking bacteria into the blood in ME/CFS and spiking inflammation. McGregor believes that gut barrier issues are probably producing many symptoms in ME/CFS.

The Tie That Binds…

McGregor then shifted gears and proposed – using a gene expression exercise study by Whistler et. al. – that the tie that binds all this together may be massive levels of something called histone deacetylation (performed by histone deacetylase enzymes or HDACs). He noted that histone acetylation/deacetylation regulated the top twenty genes found altered in Whistler’s study.   A similar outcome was found in a genetic polymorphism study.

Neil McGregor

Neil McGregor

That suggested to him that people with ME/CFS are having trouble “acetylating”; i.e. using acetyl groups to regulate our gene expression. Only one study has addressed this issue, and it found HDAC2 and HDAC3 levels three and four times higher in ME/CFS than normal.

McGregor then tied it all together with a nice bow.  Bringing us back to square one, he proposed that the HDAC problems in ME/CFS result from the problems with glycolysis.

Glycolytic inhibition, it turns out, increases HDAC activity. Low lactate and pyruvate levels – because they are HDAC inhibitors – allow HDAC levels to rise. HDAC then causes deacetylation and silences the transcription of many genes.

McGregor has found dramatically reduced urea, acetate and allantoin levels in ME/CFS. Acetate, McGregor believes, is a particularly critical factor. Acetate comes into play because it plays a crucial role in the transcription of our DNA –  and the subsequent production of protein in the cell.  The histone deacetylation he believes is present in ME/CFS inhibits DNA transcription, thus reducing protein production in the cell – which makes the cells go all twitchy when faced with a challenge.

The big question in ME/CFS, then, in McGregor’s mind is what the heck is whacking that very first stage in energy production – glycolysis. That’s where the key to this disease, he believes, will be found. He reported that he’s now searching for the causes of the glycolytic problems in ME/CFS and hopes to have more information on that this fall.

Time will tell. In the meantime, it’s good to see someone put forth a grand hypothesis of ME/CFS.

Conclusion

Neil McGregor swung for the fences (baseball reference) as he proposed that problems with the earliest aspect of energy production – glycolysis – was at the very heart of ME/CFS.  His results suggest that difficulty turning glucose and fats into energy is causing people with this disease to turn to their last and worst option – breaking down their own muscles to provide the substrates the energy production process needs.

As their tissues are broken down, the metabolites needed to replenish them are being flushed into the urine, resulting in a chronically depleted system. McGregor believes this chronic depletion of essential metabolites plays a crucial role in ME/CFS and results in numerous issues, including post-exertional malaise, gut malabsorption, connective tissue problems, inflammation and more.

The final straw of the glycolytic inhibition problem results in high levels of histone deacetylation, which impairs DNA transcription on a large scale, resulting in the broad and systemic issues found in ME/CFS.

The fix to all this requires identifying the problems with glycolysis that are setting all this off. McGregor reported he is attempting to do that now and hopes to report back in the fall.

 

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