Category: Pathophysiology

Our Evolving Understanding of ME/CFS

Abstract:

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the ‘hallmark’ symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes.

We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Source: Friedman KJ, Murovska M, Pheby DFH, Zalewski P. Our Evolving Understanding of ME/CFS. Medicina (Kaunas). 2021 Feb 26;57(3):200. doi: 10.3390/medicina57030200. PMID: 33652622. https://www.mdpi.com/1648-9144/57/3/200 (Full text)

Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load

Abstract:

Objective: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of – especially muscular -fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.

Methods: Females with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.

Results: The CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.

Conclusion: Our results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Abstract:

Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates.

In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10-4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10-4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10-3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.

Source: Missailidis D, Sanislav O, Allan CY, Smith PK, Annesley SJ, Fisher PR. Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts. Int J Mol Sci. 2021 Feb 19;22(4):2046. doi: 10.3390/ijms22042046. PMID: 33669532; PMCID: PMC7921983. https://www.mdpi.com/1422-0067/22/4/2046/htm (Full text)

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

Introduction:

Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (1, 5, 6). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (7–10). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (12, 13).

Source: Dominic Stanculescu, Lars Larsson and Jonas Bergquist. Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029 https://www.frontiersin.org/articles/10.3389/fmed.2021.628029/full (Full text)

In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range.

We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.

Source: Germain A, Levine SM, Hanson MR. In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes. 2021; 9(1):6. https://doi.org/10.3390/proteomes9010006 (Full text)

New Insights on the Role of TRP Channels in Calcium Signalling and Immunomodulation: Review of Pathways and Implications for Clinical Practice

Abstract:

Calcium is the most abundant mineral in the human body and is central to many physiological processes, including immune system activation and maintenance. Studies continue to reveal the intricacies of calcium signalling within the immune system. Perhaps the most well-understood mechanism of calcium influx into cells is store-operated calcium entry (SOCE), which occurs via calcium release-activated channels (CRACs). SOCE is central to the activation of immune system cells; however, more recent studies have demonstrated the crucial role of other calcium channels, including transient receptor potential (TRP) channels. In this review, we describe the expression and function of TRP channels within the immune system and outline associations with murine models of disease and human conditions. Therefore, highlighting the importance of TRP channels in disease and reviewing potential.

The TRP channel family is significant, and its members have a continually growing number of cellular processes. Within the immune system, TRP channels are involved in a diverse range of functions including T and B cell receptor signalling and activation, antigen presentation by dendritic cells, neutrophil and macrophage bactericidal activity, and mast cell degranulation. Not surprisingly, these channels have been linked to many pathological conditions such as inflammatory bowel disease, chronic fatigue syndrome and myalgic encephalomyelitis, atherosclerosis, hypertension and atopy.

Source: Froghi S, Grant CR, Tandon R, Quaglia A, Davidson B, Fuller B. New Insights on the Role of TRP Channels in Calcium Signalling and Immunomodulation: Review of Pathways and Implications for Clinical Practice. Clin Rev Allergy Immunol. 2021 Jan 6. doi: 10.1007/s12016-020-08824-3. Epub ahead of print. PMID: 33405100. https://pubmed.ncbi.nlm.nih.gov/33405100/

The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis

Abstract:

Background: The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is problematic due to the lack of established objective measurements. Postexertional malaise (PEM) is a hallmark of ME/CFS, and the two-day cardiopulmonary exercise test (CPET) has been tested as a tool to assess functional impairment in ME/CFS patients. This study aimed to estimate the potential of the CPET.

Methods: We reviewed studies of the two-day CPET and meta-analyzed the differences between ME/CFS patients and controls regarding four parameters: volume of oxygen consumption and level of workload at peak (VO2peak, Workloadpeak) and at ventilatory threshold (VO2@VT, Workload@VT).

Results: The overall mean values of all parameters were lower on the 2nd day of the CPET than the 1st in ME/CFS patients, while it increased in the controls. From the meta-analysis, the difference between patients and controls was highly significant at Workload@VT (overall mean: -10.8 at Test 1 vs. -33.0 at Test 2, p < 0.05), which may reflect present the functional impairment associated with PEM.

Conclusions: Our results show the potential of the two-day CPET to serve as an objective assessment of PEM in ME/CFS patients. Further clinical trials are required to validate this tool compared to other fatigue-inducing disorders, including depression, using well-designed large-scale studies.

Source: Lim EJ, Kang EB, Jang ES, Son CG. The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis. J Clin Med. 2020 Dec 14;9(12):E4040. doi: 10.3390/jcm9124040. PMID: 33327624. https://pubmed.ncbi.nlm.nih.gov/33327624/

Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: a possible approach to SARS-CoV-2 ‘long-haulers’?

Abstract:

A significant number of SARS-CoV-2 (COVID-19) pandemic patients have developed chronic symptoms lasting weeks or months which are very similar to those described for myalgic encephalomyelitis/chronic fatigue syndrome. This paper reviews the current literature and understanding of the role that mitochondria, oxidative stress and antioxidants may play in the understanding of the pathophysiology and treatment of chronic fatigue. It describes what is known about the dysfunctional pathways which can develop in mitochondria and their relationship to chronic fatigue. It also reviews what is known about oxidative stress and how this can be related to the pathophysiology of fatigue, as well as examining the potential for specific therapy directed at mitochondria for the treatment of chronic fatigue in the form of antioxidants. This review identifies areas which require urgent, further research in order to fully elucidate the clinical and therapeutic potential of these approaches.

Source: Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: a possible approach to SARS-CoV-2 ‘long-haulers’? Chronic Dis Transl Med. 2020 Nov 21. doi: 10.1016/j.cdtm.2020.11.002. Epub ahead of print. PMID: 33251031; PMCID: PMC7680046.  https://pubmed.ncbi.nlm.nih.gov/33251031/

The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms

Abstract:

Oxidative stress can be induced by various stimuli and altered in certain conditions, including exercise and pain. Although many studies have investigated oxidative stress in relation to either exercise or pain, the literature presents conflicting results. Therefore, this review critically discusses existing literature about this topic, aiming to provide a clear overview of known interactions between oxidative stress, exercise, and pain in healthy people as well as in people with chronic pain, and to highlight possible confounding factors to keep in mind when reflecting on these interactions. In addition, autonomic regulation and epigenetic mechanisms are proposed as potential mechanisms of action underlying the interplay between oxidative stress, exercise, and pain.

This review highlights that the relation between oxidative stress, exercise, and pain is poorly understood and not straightforward, as it is dependent on the characteristics of exercise, but also on which population is investigated. To be able to compare studies on this topic, strict guidelines should be developed to limit the effect of several confounding factors. This way, the true interplay between oxidative stress, exercise, and pain, and the underlying mechanisms of action can be revealed and validated via independent studies.

Source: Hendrix J, Nijs J, Ickmans K, Godderis L, Ghosh M, Polli A. The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms. Antioxidants (Basel). 2020 Nov 23;9(11):1166. doi: 10.3390/antiox9111166. PMID: 33238564; PMCID: PMC7700330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700330/  (Full text)

Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.

Results: DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.

Conclusions: Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

Source: Helliwell AM, Sweetman EC, Stockwell PA, Edgar CD, Chatterjee A, Tate WP. Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions. Clin Epigenetics. 2020 Nov 4;12(1):167. doi: 10.1186/s13148-020-00960-z. PMID: 33148325; PMCID: PMC7641803. https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00960-z  (Full study)