Watershed Paper Provides Conclusive Evidence of Underlying Pathology of ME/CFS and Fibromyalgia

The study "Adrenergic and Sensory Receptor Expression on Leukocytes Increases After Moderate Exercise in Chornic Fatigue and Fibromyalgia"  by Alan Light et. al clearly demonstrate the physiological processes behind Chronic Fatigue Syndrome.  Like many of the good papers that have come out, Dr. Light found himself having difficulty getting it published.

In simplified terms, you've got the muscles, a messenger in between, and then the recipient (nerve endings).    The situation that results in Fibromyalgia and ME/CFS is as follows:  Following muscle injury, white blood cells pick up certain chemical signals from the muscles, and pass them on to the nervous system, specifically the sympathetic nervous system.  Using currency as an example:  Excercise A produces 5 units of fatigue, and white blood cells in the muscles read 5 units of fatigue, and is supposed to pass on 5 units of fatigue to the central nervous system, but instead passes on 50 units of fatigue to the nervous system, or alternatively the white blood cells misread the signal, and pass on 50 units of fatigue to the nervous system. So in essence, the sympathetic nervous system is receiving a forged document.

How does the mechanism fit in?  In both CFS/ME and Fibromyalgia, acid-sensing ion channels, P2X4 and P2X5 purinergenic receptors, adrenergenic receptors, transient vanilloid type receptors and IL-10 were upregulated.  The only difference was that in Fibromyalgia, P2X4 (Pain signals) and TRPV1 (receptor responsible for binding capsaicin - causing burning pain) was dominant, while in CFS P2X5 (Fatigue signals) was dominant.  The effects were that changes occurred within 30 minutes of exercise in both disease cohorts, while in normal subjects, there was a considerable delayed onset, returning to baseline within 48 hrs.  The amounts measured in endurance athletes after running a marathon did not even come close to the levels attained in disease cohorts.  Incidentally, activation of P2X4 receptors has the effect of lowering blood volume, and increasing vascular resistance.

The effect is that the brain perceives the body to be under tremendous stress - it is well established that stress fundamentally disrupts the HPA axis (There is nothing better than pain for disrupting the HPA Axis!).  The brain then sends signals for bodily functions to slow down - which involves downregulating mitochondrial function.  It also means an increase in serum cortisol early on, followed by a period of adrenal fatigue.  Essentially, earlier studies on pain amplification in Fibromyalgia shed some light, but we now have a mechanism.  It was earlier thought to be as the result of too much substance P at the nervous system level.  It is mechanism that has been around since the mankind: when it hurts or when fatigued, the body sends a signal to the rest of the body to slow down.

How does this fit in with XMRV?  Much research needs to be done on this.  XMRV enters the cell via XPR1, which is a G-protein coupled receptor, which in turn invokes a reaction cascade in the cell.  Retroviruses rely on retroviral promoters to replicate once they are integrated in human DNA.  XMRV could act by enhancing the transcription of receptors involved in pain signals if the sequence of the XMRV promoter also binds to the same region that codes for pain receptors on the human genome - alternatively, XMRV triggers a signalling cascade through a G-Protein coupled receptor that upregulates pain receptors.  The effect can be further enhanced by cytokines triggered by XMRV.

These findings create optimism in finding small molecule therapeutics for both disorders, however it does not address the underlying viral pathology.    The ideal drug design target would be inhibitors of P2XR4 and P2XR5 - however the risk of side effects is always there with small molecule therapeutics.  One of the therapeutics Lyrica (Pregabalin), works by blocking pain transduction by Gabaergic mechanisms. However, it is a dirty drug, targeting other systems as well.

The Modus Operandi of XMRV: Pt1

In a 2 part series I will explain the mechanisms by which XMRV enters human cells, and possible consequences.  The cell surface receptors for XMRV have been identified as XPR1 and SYG1: XPR1 is G-protein coupled receptor suspected as a putative progesterone receptor.  The first part I will deal with deals with XPR1.

XPR1 is a membrane protein which acts as a signal transducer: it crosses the plasma membrane 7 times.  Recently, the structures of a handful of G-protein coupled receptors has been elucidated: Rhodopsin - a visual protein, Beta-adregenic receptor - adrenaline receptor and target for beta blockers, and the A2A adenosine receptor - the receptor our favorite wake up drug caffeine binds to.  XPR1 is found in a fairly diverse array of tissues: lymphocytes, hepatocytes, as well as cells in the brain, pancreas, kidney, prostate, and muscle.  This is a very important finding indeed.

It is of note that progesterone tends to shift the immune balance towards Th2, and that progesterone levels rise to as much as 10 to 15 times normal during the third trimester.  So, as a molecular biologist, it leaves me to theorize that if this virus can mimic progesterone, it can create a state that allows the immune system to ignore the virus, very much like it ignores a developing fetus - scary isn't it?  It is also worth noting that mutations in XPR1 bear a strong association with miscarriage, and that such women often bear masculine-like features.  Observations reveal that high rates of estrogen, or high rates of testosterone in the absence of progesterone tend to favor the growth of XMRV - progesterone inhibits the formation of DHT.  It seems to indicate that succeptibility to ME/CFS is strongly hormone driven, and why ME/CFS and FM are strongly female prevalent.


J. Battini, J.E. Rasko, D. Miller. (1998).  A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: Possible role in G protein-coupled signal transduction.  Proceedings of the National Academy of Sciences: