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afwijkende genen-expressie

na inspanning


toename gevoeligheid voor pijn,

het afweersysteem en

het sympathisch zenuwstelsel






Dr. Alan Light en kollega's van de universiteit van Utah hebben aangetoond dat

de genenxepressie van ME(CVS)-patiŽnten na een kleine inspanning

duidelijk afwijkt van die van gezonde mensen.


Die afwijkende genenexpressie is

al 30 minuten na de inspanning waarneembaar en

na 48 uur nog steeds aanwezig.


Die afwijkende expressie betreft met name genen (klik hier) die betrekking hebben op:

  • het signaleren van afvalprodukten (metabolieten) die, zeker in kombinatie,
  • spierpijn en -vermoeidheid doen veroorzaken: melkzuur etc.:

    m.n. de ASIC3 (klik hier), P2X4, P2X5-receptor.

  • het afweersysteem! :
  • m.n. IL-10/Th2-response, TLR4 en CD19-markers op afweercellen, bijv. makrofagen.

  • het sympathisch zenuwstelsel
  • (klik hier en hier voor een toelichting),
  • met name het afgeven en afremmen van neurotransmitters, bijv. glutamaat).

Er werd een duidelijke relatie gevonden

tussen de afwijkende genenaktiviteit en de fysieke en mentale vermoeidheid en pijn.


Van belang is nog op te merken dat

inspanning door ME(CVS)-patiŽnten de produktie van interleukine 10 (IL-10)

de vaak al aanwezige Th1Th2-shift nog verder doet versterken,

ook inflammatie het aantal ASIC3 receptoren doet verhogen (klik hier) en

de studie een klein aantal mensen betrof/op grote schaal herhaald zal moeten worden.


Deze studie toont "de onjuiste geloofsovertuiging" aan van van Houdenhove, Nijs e.a.:

  • "een onjuiste geloofsovertuiging t.a.v. pijn": klik hier.
  • "een biopsychosociale verklaring voor wijd verspreide pijn": klik hier.



Aug 09 CFIDSLink:

Breaking Research News (preview!)

Gisteren om 12:10



Blood Biomarkers for CFS: A Light at the End of the Tunnel


By Suzanne D. Vernon, PhD

Scientific Director of the CFIDS Association of America



A biomarker

is an indicator of

a biologic state used

to objectively measure processes

in the body

that occur during


disease or

in response to treatment.


Researchers studying CFS have been looking for blood biomarkers

so that

diagnosis of CFS

would not have to rely on self-reported symptoms

like fatigue,

pain and

unrefreshing sleep

that are difficult

to measure by objective means.



a consistent and reproducible blood biomarker

that could be turned into a clinical test

would be a huge leap forward for care and credibility.


Powerful molecular tools have been developed

that now allow

the activity of thousands of genes

to be examined at one time and

to quantify how much gene activity there is

by measuring the amount of message RNA (mRNA).


More than 10 CFS studies

have measured blood gene activity and

found differences between people with CFS and healthy controls,

showing promise of

an objective blood test for CFS.


However, even though investigators

found differences

between CFS subjects and

healthy controls,

there was little consistency between the 10 studies,

making it difficult

to use any of the identified gene activity differences as biomarkers.


In what could be a groundbreaking discovery for CFS,

Alan R. Light, PhD,

and his team at the University of Utah Health Sciences Center

have identified


that increase in activity

following moderate exercise.


The paper was e-published ahead of print on July 30, 2009,

and will appear in an upcoming issue of the Journal of Pain.


These results as presented in this paper

stand out as ďsmart scienceĒ for several reasons.



the investigatorsí logic

is based on mouse experiments

they conducted

to understand sensory muscle fatigue and pain.


These animal studies showed that

there are molecular receptors

that act together

to detect the metabolites

produced by muscle contraction.



the investigators used

the findings from mouse experiments

to develop

a hypothesis

for examining the blood in CFS patients and controls

to look for activity of genes

shown to detect metabolites

that result from using muscles.



they used the kind of moderate, full-body exercise

that is known to cause post-exertion fatigue in CFS

but is well-tolerated by healthy control subjects.


The study included

19 CFS patients (15 women and 4 men) and

16 matched controls (11 women and 5 men).


68 percent of the CFS patients

also met the criteria for fibromyalgia.


Each subject was asked to

exercise on an Airdyne bicycle

(uses both arms and legs to turn the wheel)

for 25 minutes.


Blood was collected

before exercise started and

again at

30 minutes,

8 hours,

24 hours and

48 hours

after exercise.


Heart rate and

perceived level of effort

were monitored

throughout the exercise challenge.


The mRNA was extracted from the blood samples and

gene activity was analyzed

using the TaqMan Gene Expression Assays

manufactured by Applied Biosystems, Inc.


In the laboratory they analyzed

metabolite-detecting genes (ASIC3, P2X4, P2X5),

adrenergic genes (A2A, B-1, B-2, COMT), and

immune system genes (IL6, IL10, TNF alpha, TLR4 and CD14).


When the investigators

compared the activity of these genes

before exercise,

there was no difference

between CFS patients and




as early as 30 minutes after exercise,

there were significant increases in gene activity for

the ASIC3, P2X4, P2X5 metabolite-detecting genes,

the B-1, B-2 and COMT adrenergic genes, and

the IL10, TLR4 and CD14 immune system genes.


The gene activity increases

persisted for up to 48 hours after exercise

in the CFS patients.


As anticipated with moderate exercise,

there was

no gene activity increase

in the healthy subjects.


The activity of these nine genes

could be used

to distinguish/identify

most of the CFS patients

from the control subjects.


These findings

confirm previous studies

that have found differences and

disturbances in

the immune system and

the hypothalamic-pituitary-adrenal (HPA) axis

and suggest that

CFS patients have problems with

sensory signaling.



this study suggests that

a blood test for muscle fatigue and pain is possible.


For these blood biomarkers to be validated,

the numbers of CFS patients and controls will have to be expanded, and

comparisons will need to be made

against subjects with other fatiguing and painful conditions.



The results reported in this paper were supported by a grant from the NIH.


In late 2008,

the Light team

was awarded a grant

from the CFIDS Association of America

to expand the number of subjects and

validate these blood biomarkers in other CFS patient populations.



You can read the summary of that study,

being led by Dr. Kathleen Light,




The Lightsí clinical collaborator is expert CFS clinician Dr. Lucinda Bateman of Salt Lake City.


Journal citation:

"Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects."

Light AR, White AT, Hughen RW, Light KC.

Journal of Pain. 2009 Jul 30. [Epub ahead of print]




Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects.

J Pain. 2009 Oct;10(10):1099-112. doi:10.1016/j.jpain.2009.06.003.

Light AR, White AT, Hughen RW, Light KC.



Chronic fatigue syndrome (CFS)

is characterized by

debilitating fatigue,

often accompanied by widespread muscle pain

that meets criteria for fibromyalgia syndrome (FMS).


Symptoms become markedly worse after exercise.


Previous studies implicated

dysregulation of

the sympathetic nervous system (SNS), and

immune system (IS)

in CFS and FMS.


We recently demonstrated that

acid sensing ion channel (probably ASIC3),

purinergic type 2X receptors (probably P2X4 and P2X5) and

the transient receptor potential vanilloid type 1 (TRPV1)

are molecular receptors

in mouse sensory neurons

detecting metabolites

that cause acute muscle pain and

possibly muscle fatigue.


These molecular receptors

are found on human leukocytes

along with SNS and IS genes.


Real-time, quantitative PCR showed that

19 CFS patients

had lower expression of

beta-2 adrenergic receptors

but otherwise

did not differ from

16 control subjects

before exercise.


After a sustained moderate exercise test,

CFS patients


greater increases than

control subjects

in gene expression

for metabolite detecting receptors

ASIC3, P2X4, and P2X5,

for SNS receptors

alpha-2A, beta-1, beta-2, and COMT and

IS genes for IL10 and TLR4

lasting from 0.5 to 48 hours (P < .05).


These increases

were also seen in

the CFS subgroup

with comorbid FMS and

were highly correlated with

symptoms of physical fatigue, mental fatigue, and pain.


These new findings suggest

dysregulation of

metabolite detecting receptors

as well as SNS

and IS

in CFS and






Muscle fatigue and pain

are major symptoms of CFS.


After moderate exercise,

CFS and

CFS-FMS patients

show enhanced gene expression

for receptors detecting muscle metabolites and

for SNS and


which correlate with

these symptoms.


These findings suggest

possible new causes,

points for intervention, and

objective biomarkers for these disorders.



PMID: 19647494




Met dank aan Brigitte die me op de studie opmerkzaam maakte.