Keech, Lloyd et al: Gene expression in response to exercise in patients with CFS

[mango]

Gene expression in response to exercise in patients with chronic fatigue syndrome: a pilot study.

Andrew Keech1*, Ute Vollmer-Conna2, Benjamin K. Barry1, 4 and Andrew R. Lloyd3

1 School of Medical Sciences, University of New South Wales, Australia
2 School of Psychiatry, University of New South Wales, Australia
3 Inflammation and Infection Research Centre, University of New South Wales, Australia
4 Neuroscience Research Australia, Australia

Front. Physiol. | doi: 10.3389/fphys.2016.00421

Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown pathogenesis, characterised by fatigue, which is exacerbated after minimal exercise.

We examined the effect of a single bout of aerobic exercise on leucocyte mRNA expression of genes putatively linked to exaggerated afferent signalling as an under-pinning of the fatigue state.

A carefully-characterised sample of patients with CFS (N = 10) and healthy matched control participants (N = 12) were included.

Participant ratings of fatigue and other symptoms, as well as blood samples, were obtained at baseline, and five other time-points up to 72 hours after 25 minutes of moderate-intensity cycling exercise. Leucocyte mRNA of 19 metabolite-sensing, adrenergic, immune and neurotransmission genes was examined using quantitative polymerase chain reaction.

Patients with CFS reported substantial fatigue, functional impairment and poor sleep at baseline (all p < 0.02), and exercise immediately induced worsened patients’ fatigue (effect size, ES = 1.17).

There were no significant changes in gene expression after exercise and patients did not differ from control participants at any time point.

Higher levels of expression of ficolin (FCN1) and a purinergic receptor (P2RX4) in patients with CFS were found when all time points were combined.

Patients with CFS did not show significant exercise-induced changes in leucocyte mRNA of 19 metabolite-sensing, adrenergic, immune and neurotransmission genes despite a prominent exacerbation of fatigue.

Keywords: mRNA, Pathogenesis, Myalgic encephalomyelitis, Post-exertional Malaise, Central sensitisation

Citation: Keech A, Vollmer-Conna U, Barry BK and Lloyd AR (2016). Gene expression in response to exercise in patients with chronic fatigue syndrome: a pilot study.. Front. Physiol. 7:421. doi: 10.3389/fphys.2016.00421

Received: 07 Jul 2016; Accepted: 06 Sep 2016.

Edited by:
Elisabeth Lambert, Baker IDI Heart and Diabetes Institute, Australia

Reviewed by:
Urs Nater, University of Marburg, Germany
Maureen Hanson, Cornell University, USA

http://journal.frontiersin.org/article/10.3389/fphys.2016.00421/abstract

 

[trishrhymes]

My first reaction to this is that the patients must have had very very mild ME. Even when I had mild ME and was still able to work part time, I couldn't have done 25 minutes of 'moderate intensity cycling exercise'. Now, at the housebound stage all this elicits is a hollow laugh.

 

[alex3619]

Tiny study, no separation of short and long term patients, and what genes were analyzed? If I can get some rest I might look into this more later, but its not on my list of priorities.

 

[Cheshire]

Given the very bad methodology of Lloyd's other study (subjective outcomes and no control group http://forums.phoenixrising.me/inde...intervention-for-cf-states.46797/#post-763392), the way he dismissed the 2 days CPET test (oh, they are not making enough effort, I don't give a shit about the respitory exchange ratio), I wouldn't trust any of his studies.

I really don't understand his trajectory, beguinning with the Dubbo study and ending with this...

 

[Chezboo]

I'm just dying to know what 'a carefully-characterised sample of patients with CFS' is. Literally on the edge of my seat, does anyone know?

 

[Sidereal]

It's Lloyd, what else could you expect.

 

[*GG*]

My first reaction to this is that the patients must have had very very mild ME. Even when I had mild ME and was still able to work part time, I couldn't have done 25 minutes of 'moderate intensity cycling exercise'. Now, at the housebound stage all this elicits is a hollow laugh.

I did the 2 day CPET test in 2010, was found Moderate, 60% of what someone my age and sex should be able to do. I am not sure what Moderate intensity cycling would mean, I probably do it though, and can do more than 25 minutes now. I rest for the following day or 2, I feel worse, but it does give me some normalcy to my life. Not sure what I would do without it.

I have exercise throughout my illness, except for 1 year, when I crashed really hard.

GG

Edit, not sure how they selected patients

 

[snowathlete]

My first reaction to this is that the patients must have had very very mild ME. Even when I had mild ME and was still able to work part time, I couldn't have done 25 minutes of 'moderate intensity cycling exercise'. Now, at the housebound stage all this elicits is a hollow laugh.

Yeah, I was moderate at the point where 5 minutes of low intensity exercise on the lowest setting, was enough to cause me to crash and become severe. So these guys doing moderate intensity for 25 minutes suggests they were mild. Also, such a small study makes it difficult to conclude anything meaningful.

 

[M Paine]

I like it. They cast a relatively wide net (leucocytes) with a set of very specific hooks (mRNA of 19 metabolite-sensing, adrenergic, immune and neurotransmission genes using PCR).

It would be interesting to know what genes were targeted, clearly they focused on certain candidates. This looks like a gene expression paper on a tight budget. One of these days, a gene expression paper is going to hit the mark.

 

[Hutan]

Higher levels of expression of ficolin (FCN1) and a purinergic receptor (P2RX4) in patients with CFS were found when all time points were combined.

Ficolins - from wikipedia:

Ficolins (Fi+Col+Lin) are a group of oligomeric lectins with subunits consisting of both collagen (Col)-like long thin stretches and fibrinogen (Fi)-like globular domains with lectin (Lin) activity usually specific for N-acetylglucosamine (GlcNAc).[1] Like collectins (Col+lectin) such as mannan-binding lectin, ficolins are secreted, lectin-type pattern recognition receptors, and similarly activate the lectin pathway of complement activation.

Examples of human ficolins include:

1. FCN1
2. FCN2
3. FCN3

Immunologist Jeak L. Ding and her team found that natural IgG (nIgG; a non-specific immunoglobulin of adaptive immunity) is not quiescent, but plays a crucial role in immediate immune defense by collaborating with ficolin (an innate immune protein).

P2RX4 from Wikipedia

P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4gene.[3][4] The product of this gene belongs to the family of purinoceptors for ATP.

The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the bladder, gastrointestinal tract, uterus, and arteries, in uterine endometrium, and in fat cells.[5] P2X4receptors have been implicated in the regulation of cardiac function, ATP-mediated cell death, synaptic strengthening, and activating of the inflammasome in response to injury.

The P2X4 receptor has been linked to neuropathic pain mediated by microgliain vitro and in vivo.[23][24] P2X4 receptors are upregulated following injury.[25] This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia.[26] BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.[27] More importantly, recent work shows that P2X4 receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.

I'd be interested to hear what the authors of this study made of the higher levels of expression of FCN1 and P2RX4. And what others (perhaps not so firmly attached to a central sensitisation theory?) might make of it.

Reviewed by:
Urs Nater, University of Marburg, Germany
Maureen Hanson, Cornell University, USA

At least we know Maureen Hanson is aware of the finding - so, if it helps build a helpful theory, I'm sure she will make use of it.

 

[halcyon]

I'm just dying to know what 'a carefully-characterised sample of patients with CFS' is. Literally on the edge of my seat, does anyone know?

Patients were drawn from a specialist tertiary care clinic for management of the disorder, having been diagnosed by a specialist according to the international criteria (Fukuda et al., 1994). As such, all patients had a relatively stable pattern of symptoms and well managed mood and sleep-wake cycle, and were deemed by their treating clinician to be able to meet the physical demands of the exercise challenge. Patients were excluded if taking medications that influence hypothalamic-pituitary axis function, autonomic nervous system function or cytokine levels (e.g. beta-blockers), or had a contraindication to participation.

Looks like they used the healthiest, most unaffected Fukuda patients they could get their hands on.

Basically they failed to replicate Light et al. 2012 which is pretty disappointing. Probably important to note that in Light's study (which also used Fukuda), 96% of the patients also met CCC.

You'd think if you were doing a study looking at PEM that you'd at least use a criteria that requires it, rather than one where it's optional. But Lloyd is involved, so no surprises here.

 

[*GG*]

Looks like they used the healthiest, most unaffected Fukuda patients they could get their hands on.

Basically they failed to replicate Light et al. 2012 which is pretty disappointing. Probably important to note that in Light's study (which also used Fukuda), 96% of the patients also met CCC.

You'd think if you were doing a study looking at PEM that you'd at least use a criteria that requires it, rather than one where it's optional. But Lloyd is involved, so no surprises here.

Ugh, that sucks!

Guess they were not Truly trying to replicate the study

GG

 

[AndyPandy]

25 minutes of cycling? The stuff of my dreams.