Comparison of differential metabolites in urine of middle school students with chronic fatigue syndrome before and after exercise

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Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2018 Apr 8;34(4):340-344 349. doi: 10.12047/j.cjap.5633.2018.078.
[Comparison of differential metabolites in urine of the middle school students with chronic fatigue syndrome before and after exercise].
[Article in Chinese]
Chi AP1, Wang ZN1, Shi B1, Yang XF1, Min RX1, Song J1.
Author information

Abstract
OBJECTIVE:
To study the differential metabolites in urine and the characteristics of metabolic pathway of middle school students with chronic fatigue syndrome (CFS) before and after exercise, and then explain the metabolic mechanism of CFS.
METHODS:
Eight male middle school students (age:17-19) with CFS were selected as the CFS group according to CFS screening criteria of the U.S. centers. At the same time, 8 male health students of the same age from the same school were selected as the control group. They were administrated to do one-time exercise on the improved Harvard step (up and down steps 30 times/min for 3minutes). Their urine was collected before and after exercise, and the differential metabolites in urine were detected by liquid chromatography-mass spectrometry (LC-MS). The multidimensional statistical methods were used to analyze the metabolites by principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA). Finally, MetPA database was used to analyze the metabolites and to construct the correlative metabolic pathways.
RESULTS:
Compared with the control group, the creatine, indoleacetaldehyde, phytosphingosine and pyroglutamic acid were selected as differential metabolites and the contents of those were decreased significantly (P<0.05 or P<0.01) in CFS group before the step movement. However, 11 differential metabolitesin CFS group were selected out after exercise, which were nonanedioic acid, methyladenosine, acetylcarnitine, capric acid, corticosterone, creatine, levonorgestrel, pantothenic acid, pyroglutamic acid, xanthosine and xanthurenic acid in sequence, the contents of methyladenosine and creatine were significantly increased (P<0.05) and the contents of the other 9 differential metabolites were significantly decreased (P<0.05 or P<0.01)compared with the control group.The 15 differential metabolites mentioned above were input MetPA database in order to analyze the metabolic pathways weighted score.The results showed that the arginine-proline metabolism pathway disorders were detected in theCFS group before exercise, the marker metabolite wascreatine. And 3 metabolic pathways disorder were detected in the CFS group after exercise, which were arginine-proline metabolism, biosynthesis of pantothenic acid and CoA, steroid hormone biosynthesis, and the marker metabolites, in turn, were creatine, pantothenic acid and corticosterone.

CONCLUSIONS:
The disorder of arginine-proline metabolic pathway is detected in CFS middle school students before exercise intervention. After exercise, it can be detected that the steroid hormone biosynthetic metabolic pathway, pantothenic acid and CoA metabolic pathways also have metabolic disorders.

KEYWORDS:
chronic fatigue syndrome; differential metabolites; metabolic pathway; middle school students; urine, metabolomics
PMID: 30788942 DOI: 10.12047/j.cjap.5633.2018.078
 

pattismith

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I cannot access to the article, is it N1- or N6-methyladenosine that was found increased?

N6-methyladenosine is found in RNA and is involved in virus replication and cancer cells development.



Abstract

N6-methyladenosine (m6A) constitutes one of the most abundant internal RNA modifications and is critical for RNA metabolism and function.

It has been previously reported that viral RNA contains internal m6A modifications; however, only recently the function of m6A modification in viral RNAs has been elucidated during infections of HIV, hepatitis C virus and Zika virus.
In the present study, we found that enterovirus 71 (EV71) RNA undergoes m6A modification during viral infection, which alters the expression and localization of the methyltransferase and demethylase of m6A, and its binding proteins.
Moreover, knockdown of m6A methyltransferase resulted in decreased EV71 replication, whereas knockdown of the demethylase had the opposite effect.
Further study showed that the m6A binding proteins also participate in the regulation of viral replication.
In particular, two m6A modification sites were identified in the viral genome, of which mutations resulted in decreased virus replication, suggesting that m6A modification plays an important role in EV71 replication.

Notably, we found that METTL3 interacted with viral RNA-dependent RNA polymerase 3D and induced enhanced sumoylation and ubiquitination of the 3D polymerase that boosted viral replication.
Taken together, our findings demonstrated that the host m6A modification complex interacts with viral proteins to modulate EV71 replication.
 

roller

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i never thought of this, but my blood/urine samples - 10 years ago - were collected after "intensive exercise" (getting to the lab, long walk with running, being too late, super toast when there...)
i drank some liters of coca cola the night i collected the urine samples. shouldnt have done, but otherwise i got nowhere. it helps me...
wondering, if this is the creatinine they are talking about.

so probably not relevant to the study, since urine sample is BEFORE exercise, blood sample AFTER exercise ?
can anyone see, if my creatinine values even contradict the study findings ?


Urine (before exercise)

2009_endocrine_bloodtest_43y.png

Blood (after exercise)

2009_endocrine_bloodtest_43y_02.png
 
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pattismith

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RESULTS:
Compared with the control group, the creatine, indoleacetaldehyde, phytosphingosine and pyroglutamic acid were selected as differential metabolites and the contents of those were decreased significantly (P<0.05 or P<0.01) in CFS group before the step movement.

However, 11 differential metabolitesin CFS group were selected out after exercise, which were nonanedioic acid, methyladenosine, acetylcarnitine, capric acid, corticosterone, creatine, levonorgestrel, pantothenic acid, pyroglutamic acid, xanthosine and xanthurenic acid in sequence, the contents of methyladenosine and creatine were significantly increased (P<0.05) and the contents of the other 9 differential metabolites were significantly decreased (P<0.05 or P<0.01)compared with the control group.78
interesting that low xanthosine could correlate with low IMP found in Levine Hanson study, and that both could be increased by Inosine intake via salvage pathway (HPRT enzyme)

1550993078715.png

https://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62635122


Interesting also that low xanthurenic acid involves tryptophane metabolism

1550993271376.png

https://www.sciencedirect.com/science/article/abs/pii/S030645221730725X
 

percyval577

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Here a (very) short cut of the Arginine - Proline - Metabolism:

Creatine <- Guanodino-acetate <-> Arginine
Other / Agmatine / Nitric Oxide < - Arginine <-> Ornithine <-> L-Glutamate 5-Semialdehyde <-> Proline --> TCA
...................................................................................................................................................v
............................................................................................................................................ Arginine


I guess when Creatine is decreased (before exercise as the article says) Arginine
is not released and is low or
is used for other puroses and is not allowed to convert into Guanodino-acetate(??)

And when Creatine is high (after exercise as the articel says) Arginine
is released and needed for some purposes or
is allowed to convert into Guanodino-acetate (??)

---

@roller I don´t understand what "24h" asf in the urine test does mean.
I am not used to read tests,
but the 46 mg/dL may be indicated to be too low (they put a "-"), maybe in reference to 0.80- 1.40g?).
The value 1.17 (after exercise?) is in the range given behind, and is normal I guess.
The creatine in blood after exercise is in the normal range which is given as 0.6-1.1.

The zeros 0.60 - 1.10 indicate that they only measure as precise as eg 0.68 or 0.69,
so they don´t be as precise as eg 0.682 or 0.687.

In conclusion - if I understood it right - you are quite a bit on the line of the article as you have been measured to be too low on creatine before exercise, as the article would like to predict.
But maybe you are not too high after exercise (the blood though ins´t investigated by the article).
 
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roller

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Study: Urine samples of CFS pupils
- before exercise: creatinine -
- after exercise: creatinine +

my results:
physical exercise/coca cola and radio-iodine treatment may have had no serious impact on my blood creatinine or "hematology" values
(urine crea after exercise is unknown)

..... ...........

i found an even older blood test (before radio iodine treatment thyroid).

2002:
blood creatinine 7.0 (no exercise)
urine creatinine 122 (no exercise)

2009:
blood creatinine 0.68 (after very intense exercise)
urine creatinine (minus)46 mg/Dl or (normal)1.17 g/24h (no exercise)

considering the different measuring units in labs, the values may be almost identical.

also, the hematology things (MCH...) appear in both panels the same almost to the dot (high, except for normal leucocytes, think thats wbc).
 
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pattismith

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I cannot access to the article, is it N1- or N6-methyladenosine that was found increased?

N6-methyladenosine is found in RNA and is involved in virus replication and cancer cells development.
Just wanted to add that N1-methyladenosine has been proposed as a urinary biomarker for several cancer types.

it was also found in Alzheimer:


Increased urinary level of oxidized nucleosides in patients with mild-to-moderate Alzheimer's disease
2006

Abstract
Objective:
Oxidative stress may play an important role in the pathogenesis of Alzheimer's disease (AD).
Design and methods:
To investigate the possible role of oxidative DNA damage in the pathogenesis of AD, we measured the metabolite concentrations of oxidized nucleosides (pseudouridine, 1-methyladenosine, 5-methylcytidine, 5-methyl-2′-deoxycytidine, 3-methyluridine, N2, N2-dimethylguanosine, 8-hydroxy-2′-deoxyguanosine, 5-deoxyadenosine and 2-deoxyguanosine) in urine between AD (n = 36) and control subjects (n = 34) using liquid chromatography-mass spectrometry (LC-MS) without urine preparation.
Results:
In AD, the 3-methyluridine, 1-methyladenosine, 8-hydroxy-2′-deoxyguanosine (p < 0.05, respectively), 2-deoxyguanosine (p < 0.01) and pseudouridine, N2, N2-dimethylguanosine (p < 0.001, respectively) were significantly increased when compared with the control subjects.
Conclusion:
The results indicate that oxidized urinary nucleosides may be useful as biomarkers for AD in early stages.
 
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This is an amazing study! I've been wanting people to check metabolites before and after exercise for such a long time, I wish more studies did this.

The lowered xanthurenic acid after exercise fits very well into the IDO trap hypothesis, as it is a metabolite of kynurenine. As for the rest of the metabolites I'm not too familiar with them, but will look into them also.

I really would like to see a replication of this, with a bigger sample size.
 
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Pantothenic acid also kinda fits with the IDO trap, because it is produced by the gut microflora, so the IDO trap worsening in the gut cells after exercise could potentially limit pantothenic acid production as well, although I'm not 100% sure.

Most of the other metabolites are pretty obscure, and I'm having trouble finding the pathways the belong to. If you guys find any, tag me.
 
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Xanthosine also maaaaaybe fits:
Decreased de novo NAD+ synthesis (which would happen in IDO-trapped cells) could possibly limit step 5 here:


But I'm really not sure of this one. It's very possible that the de novo synthesis is not significant enough to be rate limiting here, with the cell still having a lot of NAD
 

pattismith

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Xanthosine also maaaaaybe fits:
Decreased de novo NAD+ synthesis (which would happen in IDO-trapped cells) could possibly limit step 5 here:

But I'm really not sure of this one. It's very possible that the de novo synthesis is not significant enough to be rate limiting here, with the cell still having a lot of NAD
Phair already answered to that NAD concern with the metabolic try trap, he talked with some specialists about it and said that ME is not Pellagra
 

debored13

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Phair already answered to that NAD concern with the metabolic try trap, he talked with some specialists about it and said that ME is not Pellagra
NAD+/NADH ratio being off and people having good responses to NAD+ infusion does not necessarily indicate pellagra, there are many different ways NAD+ could be implicated. It could be that niacin is not deficient to the extent that it is in pellagra, but cellular redox balance is off and thus NAD+, which is so important in so so many metabolic pathways, is useful.