Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2019, Melvin, Lacerda, Nacul et al

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS.

Methods
GDF15 was measured in serum from patients with ME/CFS (n = 150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n = 150) and a cohort of patients with multiple sclerosis (n = 50).

Results
Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~ 7 months (IQR 6.7–8.8) apart, 720 pg/ml (95% CI 625–816) vs 670 pg/ml (95% CI 598–796), P = 0.5. GDF15 levels were 491 pg/ml in controls (95% CI 429–553), 546 pg/ml (95% CI 478–614) in MS patients, 560 pg/ml (95% CI 502–617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI 531–674) in
severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS.

Conclusions
Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.
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https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-02153-6

eta: can someone explain the conclusions
 
So there was "no signifcant diferences in GDF15 between ME/CFS cases with mild/moderate disease, MS cases, and healthy volunteers". And they note that
"in rodent models, increases in circulating GDF15 are reported to be associated with reduced physical activity."

Doesn't that suggest that increased GDF15 in severe ME/CFS patients reflect reduced activity and other consequences of the illness rather than the illness itself?
 
Michiel Tack said:
"in rodent models, increases in circulating GDF15 are reported to be associated with reduced physical activity."

Doesn't that suggest that increased GDF15 in severe ME/CFS patients reflect reduced activity and other consequences of the illness rather than the illness itself?
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It is not clear from the text to me. They say that physical activity leads to increased GDF-15 levels suggesting that activity puts it up. So maybe a high level suppresses further activity as a feedback - that would explain lower activity in rats with high levels.

This seems potentially a very interesting molecule to study. If ME symptoms are mediated by a signalling molecule like this then there is immediately a drug target. If this is a signal that is independent of traditional inflammatory signals then it would make a lot of sense.
 
In children with some mitochondrial diseases, blood levels of this molecule are about 11 times the normal.

Here in ME/CFS they are only slightly higher.

I am not sure but I think this suggests it will not be found to correlate well with symptom severity in ME/CFS.
 
Michiel Tack said:
So there was "no signifcant diferences in GDF15 between ME/CFS cases with mild/moderate disease, MS cases, and healthy volunteers". And they note that
"in rodent models, increases in circulating GDF15 are reported to be associated with reduced physical activity."

Doesn't that suggest that increased GDF15 in severe ME/CFS patients reflect reduced activity and other consequences of the illness rather than the illness itself?
Click to expand...

There's been a lot of talk of matching activity level between test group (ME) and control group - MS has been suggested as a control group.

@Jonathan Edwards thoughts on using MS as a control group i.e. in ME studies? Thanks in advance!
 
The the UK ME/CFS Biobank strikes again :thumbsup:

GDF15 increases with cellular stress.

GDF15 increases with exercise.

GDF15 is elevated in severe ME. Could that be suggestive of permanent cellular stress?

GDF15 is not elevated in mild/moderate ME. Would that change after an exercise challenge? Other studies looking at other markers found no big differences at rest but did find some after applying stressors. I don't think this study included any challenge (only skimmed it), so that would be an interesting next step.
 
Ravn said:
I don't think this study included any challenge (only skimmed it), so that would be an interesting next step.
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I don't think the Biobank uses exercise challenges at the moment. They do a hand grip strength test and a 10min standing test, which could cause cellular stress in some patients.

But I don't think this would show up clearly in the results because the first two times I donated to the Biobank there was no standing test, just hand grip, and it was done on a separate occasion from the blood draw (not timed to catch PEM), plus I had taken the bus and walked a bit to the first two blood draws.

For my last donation they came to my house and did the hand grip and stand test immediately before drawing the bloods.

So there aren't controls for exercise or orthostatic stress prior to the blood draw, meaning can't really draw conclusions relating to the impact of physical activity on the blood results.

I think they did this because they don't want to cause PEM. They are very careful (at least in my experience when talking to the nurse who did my blood draw), not to cause any harm to patients, so I don't think they want to intentionally cause PEM (maybe they don't have ethical approval for this).
 
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