Thoughts on: Cellular bioenergetics is impaired in patients with chronic fatigue syndrome

The big story

Significant issues with this study

Some wider questions about probing energy issues in mecfs

These results are impressive. Even with the very small control sample size (12), these are "strong data, robust to statistical correction". There's remarkable separation between patients and controls, with almost all patients below the lowest control: you don't see that too often:Corrected p values for the key measures, including basal respiration, ATP production, maximal respiration and reserve capacity, were <0.005.So these findings suggest that (white blood) cells from mecfs patients struggle to produce energy like healthy cells, and in particular can't ramp up energy production to meet increased demand. Which intuitively makes a lot of sense.(most discussed by the authors): "The primary limitation of this study was sample size which resulted in underpowered analysis", the authors plan to seek larger samples in future. There are only 3 fresh control samples so these particular findings simply reliable.: Perhaps the biggest issue is the lack of matched controls and the lack of sick controls. @alex3619 mentions specificity, the ability to separate mecfs patients from others that are sick. This is crucial both in clinical practice and for research hoping to find out what's gone wrong in mecfs. That said, it's a widespread problem in the field. (A good time to mention the UK mecfs biobank that has both large sample size and sick (MS) as well as healthy controls.)The authors say sedentary controls would be better. Activity could plausibly affect mito performance and the authors are considering measuring activity levels in future work.: the authors note the to validate these findings using other well-established measures of mitochondrial performance such as morphology and membrane potential.What makes this study so impressive is that the results are so striking, which also makes me nervous, particularly for a study using Fukuda criteria that are unlikely to identify a tightly-defined cohort. So I'd have expected a bit more variation in results, unless, say, inactivity is a major factor driving these results. Maybe I'm being unfair.One more, for geeks. Fig 3 (frozen samples) and Fig 5 (high glucose) both show data from 12 patients and 38 CFS controls, and the paper suggests they have identical conditions (frozen, 10mM glucose). So I would have expected results to be much more similar than they are (Fig 3 results are consistently lower). Am I missing something?Some people have already commented this is on PBMCs (white blood cells) and the results could be down to one sub-group such as T-cells (I'd be surprised, given how big the overall effect is). The authors did note this, and it's true of any PBMC study - which includes much mecfs work.This study found that glycolysis is normal in mecfs, while oxidative phosphorylation is the issue, while others have found glycolysis is the issue e.g. Armstrong 2015 metabolomics work, the Fluge/Mella amino acid metabolism study and the unpublished Ron Davis metabolomics work. I think earlier work by Julia NEwton's group has suggested a problem in glycolysis, or at least in pyruvate dehydrogenase at the end of glycolysis.I gather Fluge/Mella found opposite mitochondrial findings using Seahorse (does anyone have details?). @viggster said these findings are broadly in line with very early results from Seahorse in the NIH intramural study.There’s also the issue of using serum or not, the fluid that bathes the cells themselves. Potentially it carries “factors" that could be causing the problems even if the sells themselves are normal. So, I think the Fluge results on seahorse were with serum, and the Ron Davies results too. These new results are serum-free. However, it would be easy enough to test with serum using this tech, and see what happens if you swapped over healthy and patient serum.Meanwhile, the CPET 2-day exercise studies often find normal day-one results, which doesn't fit well with these results.Which is a mess in places, or the signs of an early and promising field that needs more work (and funding). I'm going with the latter for now and hope the researchers keep going with bigger and better studies. Don't forget all those UK mecfs biobank samples.