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.

I've returned

After a long hiatus, I'm back.  The last year has been rather uneventful for me - I've had opportunities to pursue research, but unfortunately with the turn of events, I found that I could not undertake research that was against my beliefs.  Science is fraught with politics, and they say the best scientists are those that are independent thinkers - Albert Einstein's theory of relativity was laughed at at first...  Same situation is happening with Judy Mikovits.  But meanwhile, I've taken on consulting work for a couple of biotech companies on contract.  But I am as passionate as ever about CFS and XMRV.

The Modus Operandi: Part II

In my previous post, I gave my theory explaining the female predominance of ME/CFS and fibromyalgia, in this post I will explain my theory behind the neurological symptoms of ME/CFS, FM, and Autism.  My theory centers around the SYG1 membrane protein, which has been identified as a synaptic guidepost, directing neurons to connect to each other.  The SYG1 protein is in the immunoglobulin superfamily, with an extracellular domain, a single transmembrane segment, and an intracellular loop.  SYG1 binds to its receptor SYG2, which is also a member of the immunoglobulin superfamily.  Ironically, SYG1 is most heavily expressed during fetal development and early childhood, and its expression greatly diminishes thereafter.  In adulthood, it continues to be expressed in the limic region (which includes the hypothalamus), at neuromuscular junctions in skeletal muscle, and in arterial walls.  When it is activated, it initiates selective synapse elination through the SCF-Ubiquitin ligase complex - when it works properly, SYG1 binds to SKR, inhibiting formation of the SCF complex (Skp1-cullin-F-Box complex), protecting nearby synapses.

It is my opinion that SYG1 dysregulation is directly correlated to symptoms noted in all three conditions: ME/CFS, FMS, and Autism.  If you disrupt proper synapse formation in early childhood development, you almost certainly will end up with a developmental disability.  It leads me to theorize as some have that XMRV is passed from mother to child through saliva, body fluids, breast milk, and quite possibly placental transmission.  Likely the process of autism begins well before the first symptoms appear, and with XMRV screening could be reversed by early use of antiretrovirals, either by treating an infected mother, or the child.  There has been some mention by Dr. Mikovits that vaccines could create the immune insult setting off autism, however I believe the risk is far, far smaller than the immune insult from getting sick - as you are only exposed to an antigen at a point in time, as opposed to receiving a continuous onslaught of viral antigen while the immune system clears the virus.

Another interesting point is that SYG1 is primarily expressed in slow sodium fibers in the peripheral nervous system at neuromuscular junctions- nerve fibers responsible for transmission of pain signals - leading to an amplified pain response.  Substance P opens slow sodium channels, and closes potassium channels - and if you've got uncontrolled synapse formation, it may very well explain some of the observations made in FMS.