Health rising blog post, by Cort Johnson, 27 Dec 2016: Fuel shortage: Norwegian study Expands on Energy Problem in Chronic Fatigue Syndrome (ME/CFS)

Fluge and Mella seem to be working at almost lightning speed. Besides managing their huge Rituximab study (and all the sub-studies within it) and the cyclophosphamide trial, they’re also carrying out large research studies.

For years, of course, some researchers and doctors championed the idea that problems with mitochondrial energy production were at the heart of ME/CFS. For many, though, the idea seemed almost too simple…too easy in a way. The body throws too many curves at us for something so obvious to be the cause. But it may be.

The work of Bob Naviaux of UCSD, Ron Davis of the Open Medicine Foundation, McGregor and Armstrong et. al. in Australia, Maureen Hanson at Cornell, and Fluge and Mella in Norway suggest that problems producing energy could, in fact, be causing the physical and mental fatigue in (ME/CFS).

Of course, it’s going to be complex. Exercise studies and other studies have suggested that the aerobic energy production pathways are severely blunted in a significant number of ME/CFS patients. Thus far, though, the metabolomics data suggests that the breakdown comes not in the aerobic energy production pathway but just before it.

Some key facts – such as I understand them.

• Key Factor in Glycolysis – Pyruvate –  Pyruvate is produced by glycolysis and then gets broken down into acetyl-CoA for use in the mitochondria. When oxygen levels are low, the same process is used to produce ATP anaerobically. Anaerobic energy gets its bad rep because it produces toxins like lactate which build up and cause pain and fatigue. All this occurs in the cell’s cytoplasm.
• Key Factor in Aerobic Energy Production – Acetyl-CoA – The first goal in aerobic energy production is to produce acetyl-CoA. This occurs in three ways: preferentially by converting pyruvate and/or by converting fatty acids or amino acids. The acetyl-CoA is then broken down further to produce ATP by a process called oxidative phosphorylation. All aerobic energy production occurs in the cell’s mitochondria.

The Study
At 302 patients (200 ME/CFS patients and 102 healthy controls) this was a nice big study. A different type of study than the recent metabolomic studies, it used a mass spectrometer to measure the levels of 20 amino acids involved in energy metabolism in the blood.

QT-RCT PCR was used to examine gene expression. Cells were also cultured, dropped in ME/CFS or healthy control’s serum (blood), tweaked with metabolic factors, and their lactate production and cellular respiration was measured.

Results
Amino Acid Results
Fluge and Mella did a simple but telling thing with the 20 amino acids by dividing them into one of three energy production pathways:

Glycolytic Amino Acids – Amino acids used in the glycolysis pyruvate producing pathway which require PDH to be metabolized (alanine (Ala), cysteine (Cys), glycine (Gly), serine (Ser), and threonine (Thr))

Aerobic Amino Acids – Amino acids that fuel aerobic energy production but which do not require PDH to be broken down((isoleucine (Ile), leucine (Leu), lysine (Lys), phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr)) – mostly ketogenic amino acids

Other Amino Acids – not found in the first category but which are essential to aerobic energy production (anaplerotic – methionine (Met), valine (Val), histidine (His), glutamine (Gln), glutamate (Glu), and proline (Pro), aspartate (Asp), (Asn + Asp = Asx))
Chronic Fatigue Syndrome (ME/CFS) – A Pyruvate Dehydrogenase Disease?

Fluge and Mella found no difference in the levels of the amino acids used in glycolysis – pyruvate production is fine – but reductions in the levels of the ketogenic amino acids used to power aerobic energy production.

Our cells much prefer using glucose to produce energy but the results and the Aussie study suggest that our cells are turning elsewhere.

Remember that our cells – use three different substrates (pyruvate, fatty acids and amino acids) to produce acetyl-CoA but they much prefer glucose.  If pyruvate isn’t being broken down into acetyl-CoA, however, then our cells will turn to another energy source; in this case amino acids. The fact that virtually all the amino acids used to produce acetyl-CoA were depleted in the female ME/CFS patients suggested that their cells, starved of metabolized pyruvate, were turning to and using up amino acids to to produce energy.

Amino acids, unfortunately, are kind of like the body’s last straw for energy production. Our cells would much prefer to use glucose, but even fatty acids are a better source of energy than amino acids. In order for body to use amino acids it has remove an amino group (producing ammonia) and turn them into a sugar.  (The fact ME/CFS patients appear to be turning to amino acids might suggest that they’re having problems with fatty acid metabolism as well.)

There’s another problem, though. If all this unused pyruvate is hanging around, it has to go somewhere. Unused pyruvate gets converted into lactate – a toxin responsible for much of the fatigue and pain associated with exercise. Lactate ultimately gets dumped into the blood stream. Fluge and Mella believe lactate accumulations are probably a key problem in ME/CFS as well. High lactate levels in ME/CFS patients’ brains have been found in several studies but reports on lactate accumulations in the blood are mixed.

Since pyruvate production doesn’t appear to be the problem, the problem must lie in the pyruvate dehydrogenase enzyme complex (PDH) which breaks down pyruvate to produce acetyl-CoA.

Or a Pyruvate Dehydrogenase Kinase Disease?
Fluge and Mella then asked why pyruvate dehydrogenase is not working in ME/CFS and may have found an answer in the increased gene expression (or activity) of the enzymes (PDH kinases (PDK)) that inhibit PDH. Rather encouragingly, they found that increased expression of one form of the PDK enzyme (PDK1) was associated with increased severity and longer duration patients.

Fluge and Mella uncovered numerous irregularities that could be affecting the pyruvate dehydrogenase enzyme in ME/CFS

Digging deeper still they found increased gene expression of the transcription factor (PPAR) which upregulates PDH kinase in ME/CFS patients as well.  Then they discovered that the gene expression levels of another enzyme (SIRT4) that limits pyruvate dehydrogenase production were increased as well.

Things were really humming along; Fluge and Mella’s findings suggested that every step in the chain needed to limit pyruvate dehydrogenase levels were activated in ME/CFS. Their consistently positive findings suggested that an inhibited PDH enzyme really may be a problem in ME/CFS.

Read more about the results of the study

Not just tired: further research suggests cell energy production impaired in ME, by Emily Beardall, 23 Dec 2016 [blog post: A Prescription for M.E. My blog from the intersection of patient & pharmacist]

TV2 interview: New study on pathological mechanisms in ME from researchers in Norway [in Norwegian, subtitles in English]

ME Action blog post: Fluge, Mella and Armstrong: more support for disordered metabolism in ME patients, by Jaime S, 23 Dec 2016