Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS, 2016, Fluge, Mella et al

[adreno]

Another important one:

Øystein Fluge, Olav Mella, et al.

Abstract

Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.

https://insight.jci.org/articles/view/89376

 

[Hutan]

Just looking at the something in the blood experiment:

However, to study the influence of possible blood-borne substances in ME/CFS pathophysiology, we investigated energy metabolism in cultured human skeletal muscle cells (HSMM) exposed to serum from 12 ME/CFS patients (including 3 patients with very severe disease and 6 patients with severe disease) and 12 healthy controls.

Basal (resting) amino acid–driven mitochondrial respiration (condition I) was moderately increased in muscle cells exposed to ME/CFS serum for 6 days (Figure 5, A and B), and this effect was also present when glucose was added (condition II). Subsequent addition of the ATP synthase inhibitor oligomycin (condition III) demonstrated that nearly all respiratory activity was linked to ATP production, confirming that the integrity of the oxidative phosphorylation system was intact in cells cultured in the presence of ME/CFS serum. There was, however, a minor increase in the remaining OCR (i.e., leak activity). Next, administration of the uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) revealed a significantly increased respiratory capacity in cells exposed to ME/CFS serum (condition IV). The data also indicated that ATP-linked respiration (difference condition II–III) and spare respiratory capacity (difference condition IV–II) were increased after exposure to ME/CFS serum (Figure 5E).

5a and b. Rates of oxygen consumption in a Seahorse analysis - black is healthy controls; red is ME/CFS


5c and d. Rates of lactate production in a Seahorse analysis


5e Calculated descriptors of mitochondrial respiration based on data from 5a.
5f Calculated descriptors of inducible lactate production based on data from 5c.

The basal glycolytic rate (condition II) was similar in cells exposed to ME/CFS and control serum (Figure 5, C and D). However, there was a trend toward reduced glucose-induced rate in the cells cultured with ME/CFS serum (difference condition II–I) (Figure 5F). In contrast, the maximum glycolytic rate in presence of oligomycin tended to be slightly increased in cells exposed to ME/CFS serum (condition III), and this trend was also present after injection of CCCP (Figure 5, C and D). Further analysis of these data revealed that the lactate production caused by oligomycin (difference condition III–II), and by CCCP (difference condition IV–II), were significantly increased in cells exposed to ME/CFS compared with control serum (Figure 5F). Therefore, the cells exposed to ME/CFS serum displayed a metabolic change involving amplified lactate production under conditions of energetic strain.

In summary, serum from ME/CFS patients with severe disease was found to increase rates of mitochondrial oxidative metabolism and respiration in muscle cells, particularly under conditions of energetic strain. Additional experiments with shorter exposure showed that the effect of ME/CFS serum on mitochondrial respiration gradually increased depending on exposure time (data not shown).

I'm prepared to believe that there were real differences between the performance of cells after exposure to ME/CFS serum, although the sample size of 12 is small.

In summary, serum from ME/CFS patients with severe disease was found to increase rates of mitochondrial oxidative metabolism and respiration in muscle cells, particularly under conditions of energetic strain. Additional experiments with shorter exposure showed that the effect of ME/CFS serum on mitochondrial respiration gradually increased depending on exposure time (data not shown).

But I don't understand the text with its qualification of the finding as applying only to patients with severe disease. Looking at the first paragraph I quoted, there were 6 people out of the 12 with "severe disease". But the analyses are done with the full 12 patients, including 3 with very severe disease and 3 with a level of disease that isn't severe or very severe. What are the authors telling us here? That the three people whose disease is not severe or worse had different results? (Two of the ME/CFS samples did seem to operate in a similar way to the healthy controls - but there's no indication of the severity levels of those samples. ) If that's true, is the serum effect a result of a sedentary lifestyle? Or is the reference to 'severe' in the text just a mistake?

It's interesting that the impact of the ME/CFS serum seemed to increase with exposure time.

 

[Hutan]

Our studies in cultured human muscle cells indicated that exposure to ME/CFS serum led to increased rates of mitochondrial respiration, driven by amino acids alone or in combination with glucose. This effect was particularly evident under conditions of energy depletion, when mitochondrial respiration works at a maximum rate (condition IV). Although lactate production tended to be low under resting conditions, it was excessively induced by energetic strain in muscle cells exposed to ME/CFS serum.

optimization of mitochondrial respiration could be regarded as a protective response to avoid energy depletion caused by PDH dysfunction. The energetic yield from such metabolic adaptation will, however, depend on the supply of energetic substrates to fuel mitochondrial respiration, which appears to be limited in ME/CFS patients. The present findings suggest that mitochondrial fueling is compromised by reduced flux through PDH, leading to overconsumption of alternative substrates such as amino acids linked to the TCA cycle. Additional studies are required to identify the substance(s) in ME/CFS serum that mediate the effects on cultured muscle cells, which could act directly on the metabolic apparatus or indirectly via signaling factors.

In conclusion, this study suggests that ME/CFS is associated with PDH impairment, leading to increased consumption of amino acids that fuel alternative pathways for ATP production. ME/CFS patient serum was found to increase mitochondrial respiration in cultured muscle cells, possibly as a compensation or adaptation to an inhibition of metabolic energy pathways.