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Discriminatory Cytokine Profiles Predict Muscle Function, Fatigue and Cognitive Function in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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Discriminatory Cytokine Profiles Predict Muscle Function, Fatigue and Cognitive Function in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) medRxiv preprint doi: https://doi.org/10.1101/2020.08.17.20164715; this version posted August 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Gusnanto A1,2, Earl KE3, Sakellariou GK3, Owens DJ4, Lightfoot A3, Fawcett S3, Owen E3, CA Staunton3, Shu T3, Croden FC1, Fenech M5, Sinclair M3, Ratcliffe L5, Whysall KA3, Haynes R1, Wells NM3, Jackson MJ3, Close GL4, Lawton C1, Beadsworth MBJ5, Dye, L1, McArdle A3. 1Human Appetite Research Unit, School of Psychology, University of Leeds, Leeds, UK; 2Department of Statistics, University of Leeds, Leeds, UK; 3Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, MRC-Arthritis Research UK and Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, UK. 4Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK; 5Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool University Hospitals Foundation Trust, Liverpool, UK. Corresponding Author Mike Beadsworth Email: [email protected] Keywords: Mitochondria, skeletal muscle, cognition, PDGF. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.08.17.20164715; this version posted August 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Significance Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, chronic, debilitating and potentially life-changing medical condition affecting children and adults of all ages, races and socio-economic groupings. Clinical presentation includes fluctuating fatigue of varying severity, with other symptoms, including myalgia, arthralgia, post-exertional fatigue, unrefreshed sleep, headache, upper respiratory tract symptoms, and cognitive impairment. With no biomarkers, or diagnostic tests, aetiology, epidemiology and pathophysiology remain unclear. This extensive study employed advanced multivariate analyses that leveraged covariation and intrinsic redundancy and identified discriminatory cytokine profiles that can be used to distinguish Healthy Controls (HCs) from patients with ME/CFS and a limited number of cytokines were associated with physical and cognitive fatigue. These findings are relevant to the potential of increasing numbers of patients developing chronic fatigue following Coronavirus disease 2019. Abstract. Myalgic Encephalomyelitis (ME) /Chronic Fatigue Syndrome (CFS) is a severely debilitating and complex illness of uncertain aetiology, affecting the lives of millions and characterised by prolonged fatigue. The initiating factors and mechanisms leading to chronic debilitating muscle fatigue in ME/CFS are unknown and are complicated by the time required for diagnosis. Both mitochondrial dysfunction and inflammation have been proposed to be central to the pathogenesis of ME/CFS. This original and extensive study demonstrated that although there was little dysfunction evident in the muscle mitochondria of patients with ME/CFS, particular blood plasma and skeletal muscle cytokines, when adjusted for age, gender and cytokine interactions could predict both diagnosis and a number of measures common to patients with ME/CFS. These included MVC and perceived fatigue as well as cognitive indices such as pattern and verbal reaction times. We employed advanced multivariate analyses to cytokine profiles that leverages covariation and intrinsic redundancy to identify patterns of immune signaling that can be evaluated for their predictions of disease phenotype. The current study identified discriminatory cytokine profiles that can be sufficiently used to distinguish HCs from patients with ME/CFS and provides compelling evidence that a limited number of cytokines are associated with diagnosis and fatigue. Moreover, this study demonstrates significant potential of using multiplex cytokine profiles and bioinformatics as diagnostic tools for ME/CFS, potentiating the possibility of not only diagnosis, but also being able to individually personalise therapies. medRxiv preprint doi: https://doi.org/10.1101/2020.08.17.20164715; this version posted August 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Introduction Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, chronic, debilitating and potentially life-changing medical condition (1). It affects children and adults of all ages, races and socio-economic groupings. Clinical presentation includes fluctuating fatigue of varying severity, with a range of other symptoms, including myalgia, arthralgia, post-exertional fatigue, unrefreshed sleep, headache, upper respiratory tract symptoms, and cognitive impairment (2). With no current biomarkers, or diagnostic tests, and sparse funding of research (3), aetiology, epidemiology and pathophysiology remain to be determined. National Institute for Health and Care Excellence (NICE) guidelines ‘confirm the lack of epidemiological data, for the UK and suggest a population prevalence of at least 0.2– 0.4%.’(1), others estimate prevalence between 0.2 and 1% (4-6). Both initiating and precipitating factors and mechanisms leading to the chronic debilitating muscle fatigue in patients with ME/CFS are unknown. There are no established biomarkers in ME/CFS, but there has been a long-standing interest in the role of the immune system in ME/CFS pathogenesis and the role that cytokines might play in disease development (7). Onset of ME/CFS often follows an acute infectious episode, particularly of infectious mononucleosis and the persistence of ‘flu-like’ symptoms has led to the suggestion that the illness is due to an inflammatory disorder (8-12). There are at least 20 ‘consensus’ clinical or research definitions for ME/CFS (13). There is heterogeneity amongst them, however, chronicity of symptoms is key to making the diagnosis. NICE guidelines suggest greater than four months, whilst the Oxford-1991 and CDC-1994-Fukuda, the most frequently used definitions in research require greater than six months. Thus, the time required for diagnosis further complicates the identification of factors responsible for initiation of ME/CFS. This is particularly relevant for skeletal muscle since several months of reduced activity causes a reduction in muscle mass and function that may compound or mask underlying aetiological factors. The mechanisms by which fatigue develops remain elusive (14, 15). Despite the issues with diagnosis of ME/CFS, it has been proposed that there is a core condition to ME/CFS that involves mitochondrial abnormalities and/or inflammation. A failure of appropriate energy supply to muscles is a fundamental and direct cause of fatigue thus it is not surprising that defective mitochondria have been implicated in conditions where fatigue is prevalent such as ageing, cardiovascular disease, neurodegenerative disorders (16) as well as ME/CFS (17). In addition to being the major source of energy for sustained muscle contractions, mitochondria generate reactive oxygen species (ROS) during normal respiration. Skeletal muscle fibres respond to contractile activity by increasing intracellular generation of superoxide and nitric oxide with the formation of secondary ROS and reactive nitrogen species (18-20). ROS scavengers have been reported to delay fatigue (21), supporting the hypothesis that physiological generation of ROS contributes to fatigue. A mouse model with aberrant mitochondrial ROS generation, the superoxide dismutase 2 knockout (SOD2KO) mouse, shows severe disturbances in exercise activity associated with increased oxidative damage and reduced ATP content in their muscle tissue (22, 23), suggesting that aberrant superoxide radical generated by mitochondria play a significant role in exercise tolerance. Mitochondrial dysfunction in the central nervous system has been implicated in a wide range of mental or neurological conditions, including chronic psychological stress and fatigue, cognitive deficits, anxiety and depression (24). Rodent studies support this, for example, mouse studies have demonstrated that mitochondrial ROS contribute to age-related cerebro-microvascular dysfunction and that preservation of mitochondria with a mitochondrial targeted antioxidant preserved memory (25). A study in rats has demonstrated chemotherapy-induced mitochondrial dysfunction was associated with cognitive impairments as well as neuropathy. Moreover, antioxidant treatment prevented the drug- induced mitochondrial changes and partially reversed the cognitive impairments (26). Whether mitochondria are abnormal in patients with ME/CFS remains the subject of considerable debate. Behan et al. (27) demonstrated substantial mitochondrial
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