Category: Pathophysiology

Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year.

Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer.

Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME.

Source: Cambras T, Castro-Marrero J, Zaragoza MC, Díez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2018 Jun 6;13(6):e0198106. doi: 10.1371/journal.pone.0198106. eCollection 2018.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991397/  (Full article)

Transient Receptor Potential Ion Channels in the Etiology and Pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling condition of unknown cause having multi-system manifestations. Our group has investigated the potential role of transient receptor potential (TRP) ion channels in the etiology and pathomechanism of this illness. Store-operated calcium entry (SOCE) signaling is the primary intracellular calcium signaling mechanism in non-excitable cells and is associated with TRP ion channels. While the sub-family (Canonical) TRPC has been traditionally associated with this important cellular mechanism, a member of the TRPM sub-family group (Melastatin), TRPM3, has also been recently identified as participating in SOCE in white matter of the central nervous system. We have identified single nucleotide polymorphisms (SNPs) in TRP genes in natural killer (NK) cells and peripheral blood mononuclear cells (PBMCs) in CFS/ME patients. We also describe biochemical pathway changes and calcium signaling perturbations in blood cells from patients. The ubiquitous distribution of TRP ion channels and specific locations of sub-family group members such as TRPM3 suggest a contribution to systemic pathology in CFS/ME.

Source: D. Staines, S. Du Preez, H. Cabanas, C. Balinas, N. Eaton, R. Passmore, R. Maksoud, J. Redmayne, S. Marshall-Gradisnik. Transient Receptor Potential Ion Channels in the Etiology and Pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. IJCM, Vol.9 No.5, May 2018. DOI: 10.4236/ijcm.2018.95038 

Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS

Abstract:

Background: Skeletal muscle fatigue and post-exertional malaise are key symptoms of Myalgic Encephalomyelitis (ME/CFS). We have previously shown that AMPK activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation, a method which induces contraction of muscle cells in vitro. The aim of this study was to assess if AMPK could be activated pharmacologically in ME/CFS.

Methods: Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or 991. AMPK activation was assessed by Western blot and glucose uptake measured.

Results: Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared to controls.

Conclusions: Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of electrical pulse stimulation to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.

Source: Brown AE, Dibnah B, Fisher E, Newton JL, Walker M. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Biosci Rep. 2018 Apr 13. pii: BSR20180242. doi: 10.1042/BSR20180242. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/29654166/

 

Metabolic features of the cell danger response

Editor’s note: Dr. Naviaux has theorized that the cell danger response lies at the heart of ME/CFS pathophysiology.

Abstract:

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal.

When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development.

An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette’s syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.

Source: Robert K.Naviaux. Metabolic features of the cell danger response. Mitochondrion. Volume 16, May 2014, Pages 7-17. https://www.sciencedirect.com/science/article/pii/S1567724913002390 (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology.

In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients.

Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Source: Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S1, Murovska M, Scheibenbogen C; European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Apr 7. pii: S1568-9972(18)30088-0. doi: 10.1016/j.autrev.2018.01.009. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29635081

Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation. We studied 98 CFS patients (21-69 years, 21 males) and 99 age- and sex-matched controls (19-65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation.

Most remarkably, CFS patients exhibited similar TSH, but lower FT3 (difference of medians 0.1%), TT4 (11.9%), TT3 (12.5%), %TT3 (4.7%), SPINA-GD (14.4%), SPINA-GT (14.9%), 24-hour urinary iodine (27.6%) and higher %rT3 (13.3%). FT3 below the reference range, consistent with the ‘low T3 syndrome’, was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% CI=1.00 – 6.54). Most observations persisted in two sensitivity analyses with more stringent cut-off values for BMI, hsCRP and WBC.

We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4 and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels.

The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of ‘non thyroidal illness syndrome’ and ‘low T3 syndrome’ experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with e.g. T3 and iodide supplements might be indicated.

Source: Begoña Ruiz-Núñez, Rabab Tarasse, Emar Vogelaar, Janneke Dijck-Brouwerand Frits Muskiet. Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study. Front. Endocrinol. | doi: 10.3389/fendo.2018.00097 https://www.frontiersin.org/articles/10.3389/fendo.2018.00097/abstract

Association of chronic fatigue syndrome with premature telomere attrition

Abstract:

Background: Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging.

Methods: Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p < 0.05.

Results: The mean T/S ratio differed significantly by illness group (p = 0.0017); the T/S ratios in CFS (0.90 ± 0.03) and ISF (0.94 ± 0.02) were each significantly lower than in NF (1.06 ± 0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist–hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1–20.5, 4.0–8.2 and 6.6–13.7 years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects < 45 years old.

Conclusions: This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS.

Source: Mangalathu S. RajeevanEmail author, Janna Murray, Lisa Oakley, Jin-Mann S. Lin and Elizabeth R. Unger. Association of chronic fatigue syndrome with premature telomere attrition. Journal of Translational Medicine201816:44© The Author(s) 2018 Received: 23 October 2017 Accepted: 16 February 2018 Published: 27 February 2018 https://doi.org/10.1186/s12967-018-1414-x (Full article)

Cellular bioenergetics is impaired in patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS. Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients.

A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls. Seven key parameters of OXPHOS were calculated: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, non-mitochondrial respiration, and coupling efficiency.

While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study (p≤0.003). The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.

Source: Cara Tomas, Audrey Brown, Victoria Strassheim, Joanna Elson, Julia Newton, Philip Manning. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One. 2017 Oct 24;12(10):e0186802. doi: 10.1371/journal.pone.0186802. eCollection 2017. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186802 (Full article)

The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic illness of unknown etiology, classified as a neurological disorder by the World Health Organization (WHO). The symptomatology of the condition appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation. This article incorporates a summary review and discussion of biomedical research considered relevant to this essential conception perspective. It is intended to provide stakeholders with a concise, integrated outline disease model in order to help demystify this major public health problem. The primary etiopathological factors presented are:

(A) Postural/biomechanical pain signaling, affecting adverse neuroexcitation, in the context of compression, constriction, strain, or damage of vertebral-regional bone and neuromuscular tissues;

(B) Immune mediated inflammatory sequelae, in the context of prolonged immunotropic neurotrophic infection-with lymphotropic/gliotropic/glio-toxic varieties implicated in particular;

(C) A combination of factors A and B. Sustained glial activation under such conditions is associated with oxidative and nitrosative stress, neuroinflammation, and neural sensitivity. These processes collectively enhance the potential for multi-systemic disarray involving endocrine pathway aberration, immune and mitochondrial dysfunction, and neurodegeneration, and tend toward still more intractable synergistic neuro-glial dysfunction (gliopathy), autoimmunity, and central neuronal sensitization.

 

Source: Glassford JA. The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front Physiol. 2017 Feb 17;8:88. doi: 10.3389/fphys.2017.00088. eCollection 2017. http://journal.frontiersin.org/article/10.3389/fphys.2017.00088/full (Full article)

 

Characteristic chemical signature for chronic fatigue syndrome identified

Chronic fatigue syndrome (CFS) is a mysterious and maddening condition, with no cure or known cause. But researchers at the University of California San Diego School of Medicine, using a variety of techniques to identify and assess targeted metabolites in blood plasma, have identified a characteristic chemical signature for the debilitating ailment and an unexpected underlying biology: It is similar to the state of dauer, and other hypometabolic syndromes like caloric restriction, diapause and hibernation.

Dauer is the German word for persistence or long-lived. It is a type of stasis in the development in some invertebrates that is prompted by harsh environmental conditions. The findings are published online in the August 29 issue of PNAS.

“CFS is a very challenging disease,” said first author Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology and director of the Mitochondrial and Metabolic Disease Center at UC San Diego School of Medicine. “It affects multiple systems of the body. Symptoms vary and are common to many other diseases. There is no diagnostic laboratory test. Patients may spend tens of thousands of dollars and years trying to get a correct diagnosis.”

As many as 2.5 million Americans are believed to have CFS. It most often afflicts women in their 30s to 50s, though both genders and all ages can be affected. The primary symptom is severe fatigue lasting at least six months, with corollary symptoms ranging from muscle pain and headaches to sleep and memory problems.

Naviaux and colleagues studied 84 subjects: 45 men and women who met the diagnostic criteria for CFS and 39 matched controls. The researchers targeted 612 metabolites (substances produced by the processes of metabolism) from 63 biochemical pathways in blood plasma. They found that individuals with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites measured were decreased, consistent with hypometabolic syndrome or reduced metabolism. The diagnostic accuracy rate exceeded 90 percent.

“Despite the heterogeneity of CFS, the diversity of factors that lead to this condition, our findings show that the cellular metabolic response is the same in patients,” said Naviaux. “And interestingly, it’s chemically similar to the dauer state you see in some organisms, which kicks in when environmental stresses trigger a slow-down in metabolism to permit survival under conditions that might otherwise cause cell death. In CFS, this slow-down comes at the cost of long-term pain and disability.”

Naviaux said the findings show that CFS possesses an objectively identifiable chemical signature in both men and women and that targeted metabolomics, which provide direct small molecule information, can provide actionable treatment information. Only 25 percent of the metabolite disturbances found in each person were needed for the diagnosis of CFS. Roughly 75 percent of abnormalities were unique to each individual, which Naviaux said is useful in guiding personalized treatment.

“This work opens a fresh path to both understanding the biology of CFS and, more importantly to patients, a robust, rational way to develop new therapeutics for a disease sorely in need of them.”

The study authors noted additional research using larger groups of participants from diverse geographical areas is needed to validate both the universality and specificity of the findings.

 

Journal Reference: Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson, Eric Gordon. Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences, 2016; 201607571 DOI: 10.1073/pnas.1607571113

 

Source: University of California – San Diego. “Characteristic chemical signature for chronic fatigue syndrome identified: Discovery, along with revealed underlying biology, could lead to faster, more accurate diagnoses and more effective, personalized therapies.” ScienceDaily. ScienceDaily, 29 August 2016. https://www.sciencedaily.com/releases/2016/08/160829163253.htm