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Moderate exercise increases expression for sensory, adrenergic and immune genes in CFS patients, but not in normal subjects
Wednesday 16 February 2011
Moderate exercise increases expression for sensory, adrenergic and immune genes in chronic fatigue syndrome patients, but not in normal subjects
1 Dept. of Anesthesiology, University of Utah Salt Lake City, UT
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 (likely ASIC3), purinergic type 2X receptors (likely 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 β-2 adrenergic receptors but otherwise did not differ from 16 controls before exercise. After a sustained moderate exercise test, CFS patients showed greater increases than controls in gene expression for metabolite detecting receptors ASIC3, P2X4 and P2X5, for SNS receptors α-2A, β-1, β-2 and COMT, and IS genes for IL10 and TLR4 lasting from 0.5–48 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 CFS-FMS.
Muscle fatigue and pain are major symptoms of CFS. Following moderate exercise, CFS and CFS-FMS patients show enhanced gene expression for receptors detecting muscle metabolites and for SNS and IS, which correlate with these symptoms. These findings suggest possible new causes, points for intervention and objective biomarkers for these disorders.
Keywords: fatigue, muscle pain, gene expression, ASIC, TRPV1, leukocytes
Chronic Fatigue Syndrome (CFS) is defined by the CDC as “persistent or relapsing fatigue not relieved by rest that severely compromises activities of daily life for 6 months or longer, for which other possible medical causes have been ruled out.” In addition, the CDC diagnosis requires at least 4 of 8 additional symptoms, including muscle pain, joint pain, tender lymph nodes, sore throat, headaches of a new type, impairment of memory or concentration, unrefreshing sleep and postexertional malaise lasting longer than 24 hours 17. One of the most common conditions comorbid with CFS is Fibromyalgia (FMS, defined by chronic widespread pain and hyperalgesia at defined tender points), with up to 70% of patients with CFS also having FMS concurrently or in the past 1. All of the symptoms of CFS and FMS are subjective, making diagnosis and treatment difficult. Clearly, objective biomarkers for these syndromes are needed.
As with other diseases of unknown etiology, one strategy to find clues for its causes is to use gene expression microarrays to determine genes that are over or under expressed in CFS patients. A few attempts have been made to determine biomarkers utilizing gene expression with small populations of CFS patients, but results to date have been mixed 3; 15; 30; 61; 78. One explanation for this discordance may be that multiple types of CFS exist, with each type having a different gene expression profile. As many as 7 subtypes of CFS have been proposed based on gene expression 6; 30. Other investigators have used a more directed approach using quantitative mRNA measurements of genes related to immune function, again with little concordance between the genes investigated 3; 46; 65.
We have followed a different strategy in our attempts to use gene expression to determine useful biomarkers for CFS and to determine factors for initiation and maintenance of this syndrome. We focused on genes that might contribute to the primary symptom of CFS, fatigue, and on two of the most common additional symptoms, muscle pain and long-lasting post-exertional worsening of symptoms.
Fatigue has many definitions, from loss of voluntary muscle contraction to the perception of “feeling tired”. However, the symptoms described in CFS, and scored in fatigue inventories more closely approaches the latter phenomenon. This “fatigue” emanates from muscles and from a unique cognitive state in the brain. This sensation of fatigue from muscles (which can occur with or without muscle pain) is caused by metabolites produced during muscle contraction and is enhanced following exhausting exercise in normal subjects. However, moderate exercise causes little long-lasting post-exercise fatigue and usually no muscle pain in normal subjects, while these symptoms are often exacerbated following even mild exercise in CFS patients 76.
To learn more about sensory muscle fatigue and pain, we conducted mouse experiments determining the types of sensory neurons that encode metabolites produced by muscle contraction. We found at least two classes of sensory neurons 37. These two classes of sensory neurons likely represent 1) sensory neurons capable of sending signals interpreted as physical fatigue, and 2) sensory neurons capable of sending signals interpreted as muscle pain. Our analysis using antagonists and agonists suggested at least 4 molecular receptors acted synergistically to detect the metabolites produced by muscle contraction. These include an Acid Sensing Ion Channel (also called Amiloride Sensitive Ion Channel) or ASIC (most likely ASIC3), 2 Purinergic X type receptors (P2X5 and/or P2X4) that are activated by ATP, and Transient Receptor Potential Vanilloid Type 1 (TRPV1) that is activated by heat, acid or endocanabinoids. The difference in coding between the “fatigue” vs. the “nociceptive” sensing pathways appeared to be related to the P2X5 vs. P2X4 receptors with P2X5 conveying the increased sensitivity needed to detect low concentrations of metabolites associated with “fatigue”. The sharing of most (but not all) molecular receptors by “fatigue” and “nociceptive” muscle afferents predicts at least some overlap between fatigue symptoms in CFS and muscle pain symptoms. Other investigators have found that ASIC3 is greatly increased by muscle and joint inflammation, which induced hyperalgesia 22; 40; 41; 75. Thus, we suggest that the primary symptoms in CFS, fatigue and muscle pain, result from enhanced activation of “fatigue” and ”nociceptive” afferents supplying muscle. It follows that increased expression of the molecular receptors encoding metabolites could be a marker of enhanced fatigue and/or muscle pain.
The sympathetic nervous system (SNS) because of its major role in regulating regional blood flow in response to the metabolite buildup in working muscles, and the immune system (IS) because of its ability to alter the sensitivity of both peripheral and central sensory pathways could also contribute to symptoms of CFS and FMS. The Hypothalamic-Pituitary-Adrenal (HPA) axis has also been implicated in the induction and maintenance of CFS. These are the same systems in which dysregulated genes have been found using micro array analysis in CFS patients 3; 6; 30; 61. Specifically, 1) adrenergic receptors may be altered in CFS (see review by Johnson et al. 26), and 2) immune cell cytokines and receptors may be altered in CFS 46; 72, although many discrepancies exist (see review by Natelson et al. 44). 3) Finally, polymorphisms in HPA axis receptor genes, and dysregulated levels of HPA hormones and expression of HPA axis genes have also been implicated in CFS 24; 59; 73.
Because circulating immune cells respond to adrenergic agonists and metabolite increases in skeletal muscle 13; 14; 33; 48; 56, and because the IS is implicated in CFS, we looked at alterations in mRNA from metabolite detecting, adrenergic, and immune function genes extracted from leukocytes of CFS patients and compared them with mRNA alterations in control subjects. Because fatigue and muscle pain in CFS and FMS are exacerbated by physical exercise to a much greater extent than in control subjects, we looked at gene expression before and after 25 minutes of mild exercise at times before, during and after we had found increased gene expression in these 3 systems in normal subjects exercising at maximal levels.
Initial experiments with normal subjects indicated that mRNA for Metabolite detecting (ASIC3, P2X4, P2X5, TRPV1), Adrenergic (α-2A, β-1, β-2, COMT), andImmune (IL6, IL10, TNFα, TLR4, CD14) was upregulated at 8 and 24 hours after strenuous exercise. The mRNA increases returned to near normal levels 48 hours after strenuous exercise 38. This time course of mRNA increases mimicked the reports of delayed onset muscle soreness (DOMS) and delayed muscle fatigue in these normal subjects. CFS patient report that even moderate exercise that does not cause DOMS or muscle fatigue in normal subjects causes physical fatigue and pain that lasts 48 hours or longer. Therefore, we tested the hypotheses that 25 minutes of moderate exercise would increase the gene expression of the aforementioned genes measured 8, 24, and 48 hours after exercise in CFS patients, but not in normal subjects. We further collected subjective measurements of fatigue and pain, and also measured some exercise physiological parameters to determine if the alterations in gene expression were related to fatigue and/or pain symptoms in CFS patients and controls.
The full article can be found here.
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