Saturday, February 19, 2011

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.


  1. Thank you, Dr. Luckett for explaining this research in terms we non-scientists understand. It's so helpful to know what's happening. Especially after the PACE results have just been released, this is great news that the Lights are finding biomarkers.

  2. I was blown away by the Light's research. It is profoundly interesting!

  3. Where is there a link to the paper?

  4. Fascinating - this model would explain such a lot.

    My ME involves fatigue and no pain. I'm curious about your reference to "small molecule therapeutics" and that Pregabalin is such a therapy for pain. I wonder if you'd like to say something about what small molecule therapeutics are and whether there's likely to be one for fatigue?

    Thanks for this post in particular and for your blog in general! Really interesting.

  5. Can you elaborate on how this works when mental activity leads to a cognitive delayed crash of thinking, concentrating? Similarly with socializing "too much"? In both cases there's no muscle mediated physical activity.

  6. Thanks for this post Dr Luckett. This might be interesting in the context, since there are many similar findings in ME and autism (and many children with autism tested so far are testing xmrv+)

    from an autism Gene Expression Profiling study:
    What is intriguing about this set of genes is that all 20 transcripts are novel and uncharacterized transcribed sequences, 19 of which map to intronic or intergenic regions. The majority of these transcripts also appear to be associated with cellular response to androgens as revealed by gene expression studies on Androgen Insensitivity Syndrome and androgen-sensitive and -insensitive prostate tumors, which are reported in GEO [Holterhus, Hiort, Demeter, Brown, & Brooks, 2003; Zhao et al., 2005]. To examine the possibility that some of these genes are androgen responsive, LCL were treated with dihydroxytestosterone, a potent metabolite of testosterone, and the levels of these transcripts were quantitated relative to vehicle-treated cells. As shown in Figure 6, all seven of the tested transcripts exhibited a response to DHT treatment. Further studies are needed to identify and fully characterize the nature of these possibly noncoding transcripts....

    Another study by the same team of researchers:

    ... In addition to gene targets associated with neurological functions, it is noteworthy that a number of the differentially expressed miRNAs also target genes involved in co-morbid disorders associated with ASD, such as muscular and gastrointestinal diseases [50-58]. Target genes of 13 miRNAs (30%) significantly dysregulated in autistic individuals were associated with skeletal and muscular diseases as well as skeletal and muscular development or function. Target genes for 12 significantly dysregulated miRNAs (28%) were associated with gastrointestinal disorders, development, and function, as well as hepatic system disease, hepatic fibrosis, and hepatic cholestasis (P < 0.05). It is interesting to note that these disorders are among the most significant biological functions and pathways enriched within the dataset of target genes, inasmuch as ASD individuals are frequently found to have co-morbid diagnoses involving muscle dysfunction (for example, muscular dystrophy, muscle weakness, and hypotonia) and digestive disorders that affect absorption and metabolism.

    Another interesting biological function associated with the miRNA gene targets is steroid hormone metabolism. More than 11% (5 out of 43) of the differentially expressed miRNAs showed an association with androgen and estrogen metabolism, as well as with estrogen receptor signaling (P < 0.05). Moreover, IPA also showed that target genes for two of the most up-regulated miRNAs - hsa-miR-376a and hsa-miR-29b - were significantly associated with circadian rhythm signaling (Fisher's exact test, P = 4.71E-03 and 1.63E-03, respectively).

  7. The cytokine abnormalities in the light study are also classical signatures of people with anxiety and are thus not ME/specific at all.

    the results could equally well be used as evidence of excercise phobia

  8. this also applies to abnormal MiRNA profiles.
    they are abnormal in anxiety and depression

    Primary Affiliation:

    Faculty of Medicine, University of Helsinki

    Title of the FIMM-Specific Research Project:

    The role of miRNAs in the regulation of anxiety


    Our research group aims to clarify genetics and molecular factors affecting normal and pathological anxiety. We are using functional genomics approaches to identify genes that regulate anxiety. Anxiety disorders are complex diseases with both genetic and environmental susceptibility factors. In this project, we will investigate whether microRNAs (miRNAs) regulate anxiety-related behavior. miRNAs are small regulatory molecules that suppress mRNA activity. They have been isolated and characterized in all organisms and tissues, and in mammalian brain they are shown to be involved in neuronal differentiation and synaptic plasticity. Resent evidence points at the involvement of miRNA expression differences in other neuropsychiatric diseases. We will carry out both miRNA and gene expression profiling from six inbred mouse strains we have studied earlier and which differ in their innate anxiety levels. We will profile two brain regions that are known to be involved in some aspects of anxiety behavior: the hippocampus and the forebrain. This enables us to investigate miRNA expression differences between strains and between brain regions, as well as to correlate these measures with gene expression, SNP, and behavioral data. miRNA expression profiling is carried out by the miRNA-seq method which we have setup for the Illumina Genome Analyzer in collaboration with the FIMM technology center. We will identify miRNAs that have an expression pattern correlating with anxiety-like behavior across the studied strains and follow up these findings by functional studies to assess the causality of these miRNAs.

  9. The P2X5 gene is non functional in humans

    P2X5 is a member of the P2X family of ATP-gated nonselective cation channels, which exist as trimeric assemblies. P2X5 is believed to trimerize with another member of this family, P2X1. We investigated the single-nucleotide polymorphism (SNP) at the 3' splice site of exon 10 of the human P2X5 gene. As reported previously, presence of a T at the SNP location results in inclusion of exon 10 in the mature transcript, whereas exon 10 is excluded when a G is present at this location. Our genotyping of human DNA samples reveals predominance of the G-bearing allele, which was exclusively present in DNA samples from white American, Middle Eastern, and Chinese donors. Samples from African American donors were polymorphic, with the G allele more frequent. Reverse transcription-polymerase chain reaction analysis of lymphocytes demonstrated a 100% positive correlation between genotype and P2X5 transcript. Immunostaining of P2X1/P2X5 stably coexpressing cell lines showed full-length P2X5 to be expressed at the cell surface and the exon 10-deleted isoform to be cytoplasmic. Fluorometric imaging-based pharmacological characterization indicated a ligand-dependent increase in intracellular calcium in 1321N1 astrocytoma cells transiently expressing full-length P2X5 but not the exon 10-deleted isoform. Likewise, electrophysiological analysis showed robust ATP-evoked currents when full-length but not the exon 10-deleted isoform of P2X5 was expressed. Taken together, our findings indicate that most humans express only a nonfunctional isoform of P2X5, which is in stark contrast to what is seen in other vertebrate species in which P2X5 has been studied, from which only the full-length isoform is known.
    PMID: 20223879 [PubMed - indexed for MEDLINE]

  10. Thank you for another great article! We are discussing your blog on mecfsforums at,5703.0.html You are most welcome to join us and participate.

    Patricia Carter
    XMRV+, 24 years M.E.

  11. Dr Luckett, I'm reposting the questions from another poster above at February 19, 2011 11:18 PM. My situation and questions are identical, would be very grateful for your reply:
    'Anonymous said...
    'Can you elaborate on how this works when mental activity leads to a cognitive delayed crash of thinking, concentrating? Similarly with socializing "too much"? In both cases there's no muscle mediated physical activity.'

    1. I think many of us would also like to know if there is an answer for this question too. There's nothing wrong with saying that research hasn't been done yet...

  12. Send it to Lancet. And when they refuse to publish it, which we KNOW they will do, ask them who is behind the curtain on making those types of decisions? Would a Weasel be involved in lancet's decisions? I'm betting a Weasel would be involved in what Lancet puts out on ME/CFS. What a medical police state the UK is. So inhumane and criminal.

  13. Dr. Luckett you are doing great work for the people who are suffering from this disease. I really wants to tell you thanks for this update.
    - Chronic Fatigue Symptoms

  14. Dr Itua cure my HIV, I have been a ARV Consumption  for 10 years. i have been in pains until i came across Dr Itua on blogs site.I emailed him about my details of my HIV and my location i explained every thing to him and he told me that there is nothing to be scared of that he will cured me, he gave me guarantee,He ask me to pay for items fees so when i'm cured I will show gratitude I did and giving testimony of his healing herbs is what I'm going to do for the rest of you out there having HIV and other disease can see the good work of Dr Itua.I received his herbal medicine through EMS Courier service who delivered to my post office within 5 working days.Dr Itua is an honest man and I appreciate him for his good work.My GrandMa called him to appreciate him and rest of my friends did too,Is a joy to me that I'm free of taking Pills and having that fat belle is a will understand what i'm talking about if you have same problem I was having then not now though.I'm free and healthy Big Thanks To Dr Itua Herbal Center.I have his calendar too that he recently sent me,He Cure all kind disease Like,Cancer,Weak Erection,Wart Remover,Hpv,Herpes,Alzheimer’s disease,Bechet’s disease,Crohn’s disease,Cushing’s disease,Heart failure,Multiple Sclerosis,Hypertension,Fibromyalgia,Hiv,Hepatitis B,Liver/Kidney Inflamatory,Epilepsy,Blood Cancer,Prostate Cancer,Colo-Rectal Cancer,Brain Cancer,Lung Cancer,Infertility,Parkinson's disease,Schizophrenia,Lung Cancer,Breast Cancer,Colo-Rectal Cancer,Blood Cancer,Prostate Cancer,siva.Fatal Familial Insomnia Factor V Leiden Mutation ,Epilepsy Dupuytren's disease,Desmoplastic small-round-cell tumor Diabetes ,Coeliac disease,Creutzfeldt–Jakob disease,Cerebral Amyloid Angiopathy, Ataxia,Arthritis,measles, tetanus, whooping cough, tuberculosis, polio and diphtheriaAmyotrophic Lateral Scoliosis,Fibromyalgia,Fluoroquinolone ToxicitySyndrome Fibrodysplasia Ossificans ProgresSclerosis,Seizures,Alzheimer's disease,Adrenocortical carcinoma.Asthma,Allergic diseases.Hiv_ Aids,Herpe ,Copd,Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Lung disease.Enlarged prostate,Osteoporosis.Alzheimer's disease,
    Dementia.Fibroid,Diabetes,Dercum,Copd ,and also Bring back Ex Lover Back..Here his Contact  Or Whats_app Number +2348149277967