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In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

A.B.

Senior Member
Messages
3,780
A theoretical paper from the Institute for Condensed Matter Physics, Technische Universität Darmstadt, Germany. Authors: Nicor Lengert, Barbara Drossel.

Abstract
Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients. To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.

http://www.sciencedirect.com/science/article/pii/S0301462215000630

@alex3619 might be interested in this.
 

Helen

Senior Member
Messages
2,243
Thanks @A.B. It would be interesting to read the full article but I guess it´s only available behind the pay-wall.
 

drob31

Senior Member
Messages
1,487
This probably why baking soda helps some people.

So, supplement list:

MitoQ or PQQ
and baking soda
 

Sidereal

Senior Member
Messages
4,856
According to their model

But it should be considered that the very low ATP minimum below 50% of the resting value in CFS simulations would probably lead to cell damage and prevent the CFS patients from maintaining the power output simulated in the 30 s exercise scenario. The simulation of a repeated exercise after 24 h demonstrates that if the long recovery periods are not adhered to, it leads to cumulative effects amplifying the symptoms of PEM for recovery times as long as 61 hours.

This is in line with our own experiences of prolonged overexertion leading to cumulative PEM damage, sometimes permanent.
 

Sidereal

Senior Member
Messages
4,856
When the ATP demand exceeds the supply during exercise, the adenylate kinase converts two ADP to one ATP and AMP, thereby stabilizing the ATP/ADP ratio and thus the free Gibbs energy gained from ATP hydrolysis. Due to the high AMP levels and reduced pH the IMP producing activity of the AMP deaminase is upregulated and thereby ensures the stabilizing effect of adenylate kinase to be continued. Furthermore, one H+ is absorbed during the reaction, which counteracts the advancing acidification, but increases the amount of IMP degraded to inosine and hypoxanthine and finally uric acid. The temporary benefit, which can be essential for survival, comes at a high price: The reduction of the total adenine nucleotide pool, the recovery of which can take hours or days of rest. After high energy demand over a long period without sufficient rest even athletic subjects need more than 72 hours to replenish their adenine nucleotide pool [64, 65].

If I understand this right, when we try to exercise we're ripping through our protein in order to survive.

Investigating the mitochondria in neutrophils of CFS patients, two subgroups have been reported, which have been differentiated by the way the mitochondrial deficiency is compensated [6]. It was proposed that one of the groups compensates the lower aerobic ATP synthesis rate by upregulating glycolysis, the other however, seemed to use an alternative pathway, probably by increasing the purine nucleotide degradation. Our model reproduces the features of both groups and the proportion between both compensatory mechanisms can be changed by modifying the activation dynamic of glycolysis and the kinetics of purine nucleotide degradation. In the simulations presented however, the corresponding parameters were determined by experimental values of healthy subjects.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
This appears (without reading the full paper) to be plausible, but is only formally restating what is already in the literature, and then modelling it. It requires real world validation. However its good to see such models. I think they are important steps forward, and give us predictions that can be tested.

I do not recall reading the term "in silico" before. It seems appropriate.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
What's this pool, and is there any way to fill it faster?
Turn the tap on? (Sorry, I couldn't resist.)

I'm trying to get my head around all these metabolic pathways, but they're really complicated. I think it might be referring to the mix of certain metabolites that incorporate adenine, and I've seen it specifically being used to refer to ATP+ADP+AMP. I'm not sure if it can also refer to other nucleotides that incorporate adenine such as NAD (nicotinamide adenine dinucleotide).
 
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Messages
4
Location
Darmstadt, Germany
I'm the author of this article. I am happy to see it being discussed already here. If you are interested, the full text is available for free from here:
http://authors.elsevier.com/a/1QuQW14YsaFG8s until June,8 (after that just write me a mail).

The paper about EBV inducing CFS has a really interesting approach. Does anyone know the percentage of CFS patients with preceding EBV infection (I am one of those)?

This appears (without reading the full paper) to be plausible, but is only formally restating what is already in the literature, and then modelling it. It requires real world validation.

I agree that most of the qualitative predictions can be made from the already available literature, but still, the paper leads to a better understanding on a biochemical level and to quantitative statements. E.g. it shows that the reaction 2 ADP->ATP+AMP does not contribute much to the energy supply (as often stated) but it mainly stabilizes the free Gibbs energy gained from ATP hydrolysis. Also, it can make predictions about the recovery time, which hopefully will be compared to experimental data some day.

What's this pool, and is there any way to fill it faster?

Well, it was shown that ribose leads to a slightly faster recovery. On the other hand, permanent high ribose level might be harmful because of glycation of proteins. So I would take it only during PEM or before any higher energy demand. The problem is that the low mitochondrial capacity may be the cause of PEM but itself is probably caused by immunological dysfunctions like an upregulated RNase L pathway or a dysfunction in the memory cells to EBV. So supplementing with ribose, Q10, carnitine etc. can improve the symptoms a bit but does not remove the underlying cause.
 
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rosie26

Senior Member
Messages
2,446
Location
NZ
Well, it was shown that ribose leads to a slightly faster recovery. On the other hand, permanent high ribose level might be harmful because of glycation of proteins. So I would take it only during PEM or before any higher energy demand. The problem is that the low mitochondrial capacity may be the cause of PEM but itself is probably caused by immunological dysfunctions like an upregulated RNase L pathway or a dysfunction in the memory cells to EBV. So supplementing with ribose, Q10, carnitine etc. can improve the symptoms a bit but does not remove the underlying cause.
Welcome to PR, great to have you here! Thanks for your for your cautious guide on taking ribose. I will feel more comfortable taking ribose that way from now on. It does help to take some rough edges off PEM for me.
 

Gijs

Senior Member
Messages
690
Great report Corni. I know a lot of patients who have used D-Ribose. Some experienced an improvement (not strong) but many supplements provide one improvement in ME patients. Even though they are not signifcant improvements still I wonder why patients respond so strongly to supplementation. Much more interesting for me is what causes 'mitochondrial dysfunction' or reduced energy metabolisme, could it be due to low bloodflow or gut problems... it is very complicated.
 

jimells

Senior Member
Messages
2,009
Location
northern Maine
I'm the author of this article. I am happy to see it being discussed already here.

Thank you for joining the discussion of your paper. We are always hungry for new papers, and they always get a thorough, but fair, examination. Personally, I can barely understand most of this stuff. But I always enjoy following the discussion (as best I can) among some of the smartest folks in the world. :thumbsup: