Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction. Here, we evaluated patients' symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls. We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being. This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels. Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

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Potential of Activin B as a Clinical Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Biomolecules ◽

10.3390/biom11081189 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1189

Author(s):

Sabine Gravelsina ◽

Zaiga Nora-Krukle ◽

Anda Vilmane ◽

Simons Svirskis ◽

Katrine Vecvagare ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Complex Disease ◽

Clinical Symptoms ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Age Related ◽

Diagnostic Potential ◽

Clinical Biomarker

Reliable serum biomarkers are of immense need for diagnostic purposes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a disabling and complex disease for which diagnosis is mainly based on clinical symptoms. The aim of this study was to evaluate a possible diagnostic potential of activin B by directly comparing 134 cases of ME/CFS with 54 healthy controls. Analyses of human activin B level in plasma samples were performed using a validated human activin B ELISA assay. The results of the study show that activin B levels did not differ statistically significantly between ME/CFS patients and healthy controls (p = 0.6511). No gender or age-related differences in activin B levels were observed in the ME/CFS group and healthy controls. The level of activin B tended to decrease with increasing visual analogue scale score (r = −0.2004; p = 0.5085) nevertheless the results obtained so far does not support the clinical utility of activin B as a biomarker for ME/CFS.

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A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

10.21203/rs.3.rs-52172/v1 ◽

2020 ◽

Author(s):

Eiren Sweetman ◽

Torsten Kleffmann ◽

Christina Edgar ◽

Michel de Lange ◽

Rosamund Vallings ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Differentially Expressed ◽

Control Group ◽

Peripheral Blood Mononuclear ◽

Fatigue Syndrome ◽

Ms Analysis

Abstract Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.Methods: To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group. Results: A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation. Conclusions: The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

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Living with myalgic encephalomyelitis/chronic fatigue syndrome: Experiences of occupational disruption for adults in Australia

British Journal of Occupational Therapy ◽

10.1177/03080226211020656 ◽

2021 ◽

pp. 030802262110206

Author(s):

Chelsea Bartlett ◽

Julie L Hughes ◽

Laura Miller

Keyword(s):

Chronic Fatigue Syndrome ◽

Lived Experience ◽

Well Being ◽

Chronic Fatigue ◽

Health Condition ◽

Myalgic Encephalomyelitis ◽

Structured Interviews ◽

Personal Support ◽

Fatigue Syndrome ◽

Occupational Participation

Introduction Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood, highly stigmatised health condition that has widespread impacts on the individual. Currently, there is limited understanding of the ME/CFS experience from an occupational perspective within Australia. This study aimed to explore the lived experience of ME/CFS and subsequent disruption to occupational participation for adults living in Australia. Methods Using descriptive case study design, five participants with ME/CFS in Australia completed semi-structured interviews. Reflexive thematic analysis was used to analyse the qualitative data. Findings Themes identified were organised using the Person-Environment-Occupation model. Participants reported systemic changes to previous levels of physical, cognitive and affective functioning, resulting in significant occupational disruption and poor well-being. Occupational prioritisation was followed by a loss of occupations starting with leisure, then productivity and eventually self-care. Environmental barriers to participation included stigma and misunderstanding of ME/CFS, financial hardship, lack of appropriate health services and strains on personal support networks and relationships. Conclusion Changes to occupational performance following the onset of ME/CFS caused significant occupational disruption and resulted in limited participation which narrowed over time. There is a clear role for occupational therapy to intervene early to prevent significant negative impacts on occupational participation for people with ME/CFS.

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Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

10.1101/237958 ◽

2017 ◽

Author(s):

Santiago Herrera ◽

Wilfred C. de Vega ◽

David Ashbrook ◽

Suzanne D. Vernon ◽

Patrick O. McGowan

Keyword(s):

Chronic Fatigue Syndrome ◽

Complex Disease ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Genetic Interactions ◽

Unknown Etiology ◽

Immune Functioning ◽

Fatigue Syndrome ◽

Close Proximity

ABSTRACTMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an example of a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as with specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, the association between DNA methylation and genetic background in relation to the ME/CFS is currently unknown. In this study we explored this association by characterizing the genomic (~4.3 million SNPs) and epigenomic (~480 thousand CpG loci) variability between populations of ME/CFS patients and healthy controls. We found significant associations of methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism. Finally, we found significant correlations of genotypes with methylation phenotypes associated with ME/CFS. The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS.

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The functional status and well being of people with myalgic encephalomyelitis/chronic fatigue syndrome and their carers

BMC Public Health ◽

10.1186/1471-2458-11-402 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 47

Author(s):

Luis C Nacul ◽

Eliana M Lacerda ◽

Peter Campion ◽

Derek Pheby ◽

Maria de L Drachler ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Functional Status ◽

Well Being ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Fatigue Syndrome

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A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

Journal of Translational Medicine ◽

10.1186/s12967-020-02533-3 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 2

Author(s):

Eiren Sweetman ◽

Torsten Kleffmann ◽

Christina Edgar ◽

Michel de Lange ◽

Rosamund Vallings ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Differentially Expressed ◽

Control Group ◽

Peripheral Blood Mononuclear ◽

Fatigue Syndrome ◽

Ms Analysis

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology. Methods To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group. Results A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation. Conclusions The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

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Patients’ hopes for recovery from myalgic encephalomyelitis and chronic fatigue syndrome: Toward a “recovery in” framework

Chronic Illness ◽

10.1177/1742395318815965 ◽

2018 ◽

Vol 16 (4) ◽

pp. 307-321

Author(s):

Andrew R Devendorf ◽

Abigail A Brown ◽

Leonard A Jason

Keyword(s):

Chronic Fatigue Syndrome ◽

Outcome Research ◽

Treatment Options ◽

Well Being ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Structured Interviews ◽

Fatigue Syndrome ◽

Patient Voice

Objective There is no consensus on recovery from myalgic encephalomyelitis and chronic fatigue syndrome, which has spawned debates when interpreting outcome research. Within these debates, the patient voice is often neglected. This study aimed to understand how patients conceptualize recovery – regarding the definition and possibility of recovery. Method We conducted in-depth, semi-structured interviews with 10 older (above age 50) female patients with myalgic encephalomyelitis or chronic fatigue syndrome. Data were analyzed using a deductive thematic analysis. Results Our sample viewed recovery as functioning without fear of relapse, returning to previous roles and identities, and achieving a sustained absence of symptoms. Participants expressed skepticism that reaching recovery from myalgic encephalomyelitis and chronic fatigue syndrome exists but working toward significant improvement through coping is a viable goal. Although many accepted they would never reclaim full functioning, participants continued to experience uncertainty about their future with unclear prognostic goals and limited treatment options. Discussion Recovery is more than just symptom reduction. Outcome research should incorporate well-being measures like identity, meaning and quality of life, and personal empowerment to enhance recovery definitions. When communicating treatment goals, providers might convey cautious optimism for complete symptom remission, while emphasizing that living a fulfilling life through effective coping strategies is possible.

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The psychological impact of dependency in adults with chronic fatigue syndrome/myalgic encephalomyelitis: A qualitative exploration

Journal of Health Psychology ◽

10.1177/1359105316643376 ◽

2016 ◽

Vol 24 (2) ◽

pp. 264-275 ◽

Cited By ~ 4

Author(s):

Ashley Mai Williams ◽

Gary Christopher ◽

Elizabeth Jenkinson

Keyword(s):

Chronic Fatigue Syndrome ◽

Psychological Impact ◽

Well Being ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Structured Interviews ◽

Psychological Well Being ◽

Self Identity ◽

Fatigue Syndrome ◽

Qualitative Exploration

Chronic fatigue syndrome/myalgic encephalomyelitis can limit functional capacity, producing various degrees of disability and psychological distress. Semi-structured interviews explored the experiences of adults with chronic fatigue syndrome/myalgic encephalomyelitis being physically dependent on other people for help in daily life, and whether physical dependency affects their psychological well-being. Thematic analysis generated six themes: loss of independence and self-identity, an invisible illness, anxieties of today and the future, catch-22, internalised anger, and acceptance of the condition. The findings provide insight into the psychological impact of dependency. Implications for intervention include better education relating to chronic fatigue syndrome/myalgic encephalomyelitis for family members, carers, and friends; ways to communicate their needs to others who may not understand chronic fatigue syndrome/myalgic encephalomyelitis; and awareness that acceptance of the condition could improve psychological well-being.

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Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

10.20944/preprints201907.0196.v1 ◽

2019 ◽

Author(s):

Daniel Missailidis ◽

Sarah Annesley ◽

Paul Fisher

Keyword(s):

Chronic Fatigue Syndrome ◽

Complex Disease ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Patient Treatment ◽

Symptom Presentation ◽

Many Body ◽

Fatigue Syndrome ◽

Many Body Systems ◽

Biomedical Investigation

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

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Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Diagnostics ◽

10.3390/diagnostics9030080 ◽

2019 ◽

Vol 9 (3) ◽

pp. 80 ◽

Cited By ~ 14

Author(s):

Daniel Missailidis ◽

Sarah J. Annesley ◽

Paul R. Fisher

Keyword(s):

Chronic Fatigue Syndrome ◽

Complex Disease ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Neurological Dysfunction ◽

Patient Treatment ◽

Many Body ◽

Fatigue Syndrome ◽

Many Body Systems ◽

Biomedical Investigation

The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift. Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

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