Patients with [CFS] performed worse than controls in a controlled repeated exercise study despite normal oxidative phosphorylation, 2010, Vermeulen +

Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity
Vermeulen, Ruud CW; Kurk, Ruud M; Visser, Frans C; Sluiter, Wim; Scholte, Hans R

Background
The aim of this study was to investigate the possibility that a decreased mitochondrial ATP synthesis causes muscular and mental fatigue and plays a role in the pathophysiology of the chronic fatigue syndrome (CFS/ME).

Methods
Female patients (n = 15) and controls (n = 15) performed a cardiopulmonary exercise test (CPET) by cycling at a continuously increased work rate till maximal exertion. The CPET was repeated 24 h later. Before the tests, blood was taken for the isolation of peripheral blood mononuclear cells (PBMC), which were processed in a special way to preserve their oxidative phosphorylation, which was tested later in the presence of ADP and phosphate in permeabilized cells with glutamate, malate and malonate plus or minus the complex I inhibitor rotenone, and succinate with rotenone plus or minus the complex II inhibitor malonate in order to measure the ATP production via Complex I and II, respectively. Plasma CK was determined as a surrogate measure of a decreased oxidative phosphorylation in muscle, since the previous finding that in a group of patients with external ophthalmoplegia the oxygen consumption by isolated muscle mitochondria correlated negatively with plasma creatine kinase, 24 h after exercise.

Results
At both exercise tests the patients reached the anaerobic threshold and the maximal exercise at a much lower oxygen consumption than the controls and this worsened in the second test. This implies an increase of lactate, the product of anaerobic glycolysis, and a decrease of the mitochondrial ATP production in the patients. In the past this was also found in patients with defects in the mitochondrial oxidative phosphorylation. However the oxidative phosphorylation in PBMC was similar in CFS/ME patients and controls. The plasma creatine kinase levels before and 24 h after exercise were low in patients and controls, suggesting normality of the muscular mitochondrial oxidative phosphorylation.

Conclusions
The decrease in mitochondrial ATP synthesis in the CFS/ME patients is not caused by a defect in the enzyme complexes catalyzing oxidative phosphorylation, but in another factor.

Link | PDF (Journal of Translational Medicine)

 

Another older paper, that I couldn't find listed, but is mentioned in the NICE 21 Guideline review from 2019 here.

 

It looks as if the CK was measured before the first and second CPETs, so we only have measures of CK at 0 and 24 hours after the first CPET.

 

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[38] Impaired oxygen delivery to muscle in chronic fatigue syndrome (1999, Clinical Science) mentioned here (also by @DokaGirl)

 

Is there a way that muscle damage (impaired oxphos) could be happening such that creatine kinase is liberated from muscle cells, but not being picked up in blood?

Two possibilities come to mind:

1) The CK rise in blood is impeded
2) The CK is sponged in the blood or other tissues.

If oxygen transfer is genuinely impeded: capillary -> muscle cell, then CK transfer into the blood pool might also be impeded: interstitium -> capillary.

Note that in Eccentrically Induced Skeletal Muscle Damage in Patients With Chronic Fatigue Syndrome CFS, With Reference to Overtrained Athletes (1995) they showed that the peak plasma concentration of CK was 1) much higher in patients 2) peaked at day 4 3) showed a relatively delayed rise in patients early on.

They measured at day 1, 2, 4, 6, 8, 12 ... so possibly either HC or ME could have peaked at day, 3, 4 or 5 and been offset from each other.



This is normalised CK as a %. Patients and HCs peak at the same time although the absolute CK rise was much higher in patients. The patients are slower to rise (relatively) and quicker to decay but the difference in rise time is much more than the difference in decay.

At day 2 HCs are at 50% of their peak, ME is at 10%.

This might raise the possibility that something is impeding CK getting into the blood pool, but once there it clears closer to normal (though perhaps more efficiently than HCs).

 

What could impede oxygen transfer from capillary to muscle cell or CK back to capillary?

In Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles (2023, Acta Neuropathologica Communications) —

(Biopsies performed at rest, not after CPET.)

Do we have anything similar in the ME/CFS literature? Do we know if myoglobin and aldolase are downregulated in muscle? (I wonder if impaired oxygen availability would reduce their need, so again they didn't show up in blood tests).

 

The huge appeal of defects in energy metabolism playing central role is that they can explain the mental as well as the physical fatigue. But they all seem to have the same problem that they can’t explain why a single maximal exercise test produces normal results compared with sedentary controls. Certainly normal compared with the Level of impairment.

 

Yes, I've also been wondering if the explanation for some of the heterogeneity in findings related to metabolism might be due to a non-specific fuel starvation issue that can be compensated at cellular level by multiple strategies. This might vary by tissue and between individuals dependent on genetics, diet, co-morbidities etc.

If the reduction in capillary density and the (possibly more important) increased capillary basement membrane thickness is a replicated finding across ME/CFS then I'd wonder if it was muscle-specific or at least muscle-dominant. Ie it might depend on the macrophage infiltration they're showing which wouldn't be the case in brain.

I can imagine a scenario where the relative severity of capillary changes might change the symptom spectrum: maybe more or less myalgia, fatiguability, cognitive dysfunction. (Maybe BBB disruption is more at play in the brain, rather than any capillary BM thickening.)

I would be interested to see the 1995 thesis protocol replicated but more fine-grained, eg daily CK and aldolase measurements for 7 days, to see if there's actually a separation in timing of the peaks. Presumably this could be up to 48 hours if HCs actually peaked at 3 days and ME peaked at 5 days.