Robert 1973
Senior Member (Voting Rights)
There's one thing that's tying my brain into knots with studies like this one which point towards a failure of ME cells to mount an appropriate response to exertion. Why don't these studies show any difference at rest/baseline? We're most categorically ill all of the time, albeit more severely with PEM - so surely something must be measurably different already at baseline. Why does this not show up in the metobolomics?
Other studies have led to hypotheses that ME cells are stuck in a cell danger response or that they're exhausted (immune cells) or that they're running at full capacity and with all compensatory mechanisms switched on already at rest, or all of the above, and that the cells therefore are unable to respond to further demand. Which would fit the findings here that ME cells simply do nothing in response to exercise. But I would expect all of the hypotheses to impact metabolism at baseline as well as after exertion. So why do our baseline metabolomes look so seemingly normal? What are we missing? Something the tests aren't measuring? Yet they do throw up all manner of unidentified compounds. Or are the sort of pwME who participate in CPET studies so mild they're actually as well as the general population between episodes of PEM? That sounds unlikely to me.
The apparently normal baseline urine metabolite data makes me* think that an abnormality with the process of excreting the metabolites may be a more likely explanation for these results. If that were the case, presumably that would have have other knock-on or downstream effects.
[* Edit: as a layperson who has a very limited understanding of the science.]
I note that the paper concludes:
Future work will include expanding this study to a much larger cohort that includes both sexes to validate these results, examine sex differences in the urine metabolome, and explore whether there are more subtle differences in urinary metabolites in ME/CFS patients at baseline that could potentially contribute to a diagnostic test for the disease in the future.
Apologies if this has already been highlighted (I’ve not managed to read the whole of this thread yet) but another interesting part of the paper which caught my eye was this (my bold):
“Four compounds in the urea cycle; arginine and proline metabolism subpathway are changing differently after exercise in the ME/CFS patients and controls: carboxy-methylarginine, proline, symmetric dimethylarginine (SDMA), and dimethylarginine (ADMA) (Figure 6A). Proline is a building block of collagen and is therefore a key component of connective tissues. SDMA and ADMA are both regulators and competitive inhibitors of nitric oxide (NO) production. NO aids in vascular maintenance in healthy individuals [33], and decreased NO production is associated with endothelial dysfunction and cardiovascular disease [34]. ADMA can be removed through urinary excretion or it can be degraded in the liver [35]. The increased excretion of SDMA and ADMA in controls but not in patients after exercise implies that controls may be removing excess NO synthase inhibitors in order to maintain vascular homeostasis and that this beneficial adaptation to exertion may not be occurring in patients. The relationship of NO and ME/CFS is unclear; plasma from ME/CFS subjects at baseline was found to induce less NO production by endothelial cells in vitro [36], but it is unknown whether or not that was due to higher levels of ADMA or SDMA in ME/CFS plasma, as they were not measured in that study and NO regulation is complex.”
This study and the recent studies on endothelial dysfunction, which appear to show abnormal NO production in response to exertion, have given me renewed hope that real progress may be starting to be made in understanding some of the mechanism. Am I being too optimistic? (If I am, please be gentle – I need every bit of hope I can get at the moment.)
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