Category: Pathophysiology

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest

Abstract:

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where symptoms worsen with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities. Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls.

Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients exhibited respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake.

Patients with long COVID and ME/CFS did not have muscle atrophy, but had less capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS.

Source: Braeden T. Charlton, Anouk Slaghekke, Brent Appelman, Moritz Eggelbusch, Jelle Y. Huijts, Wendy Noort, Paul W. Hendrickse, Frank W. Bloemers, Jelle J. Posthuma, Paul van Amstel, Richie P. Goulding, Hans Degens, Richard T. Jaspers, Michèle van Vugt, Rob C.I. Wüst. Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest. medRxiv 2025.05.02.25326885; doi: https://doi.org/10.1101/2025.05.02.25326885 https://www.medrxiv.org/content/10.1101/2025.05.02.25326885v1.full?_x_tr_sl=nl&_x_tr_tl=en&_x_tr_hl=en (Full text)

Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness characterized by post-exertional malaise (PEM), a worsening of symptoms following exertion. The biological mechanisms underlying PEM remain unclear. Extracellular vesicles (EVs) play a key role in cell-cell communication and may provide insight into ME/CFS pathophysiology post-exertion. Emerging evidence suggests similarities between ME/CFS and Long COVID, including PEM and overlapping immune and metabolic dysfunctions, highlighting the need for deeper mechanistic understanding.

Methods: This study explores the EV proteome response to exercise in 10 males with ME/CFS and 12 well-matched sedentary male controls. Participants underwent a maximal cardiopulmonary exercise test, and plasma samples were collected at baseline, 15 min, and 24 h postexercise. EVs were isolated from plasma using size-exclusion chromatography and characterized with nanoparticle tracking analysis. EV protein abundance was quantified with untargeted proteomics (nanoLC-MS/MS). Comprehensive analyses included differential abundance, pathway enrichment, protein-protein interaction networks, and correlations between EV protein dynamics and clinical or exercise physiology data.

Results: ME/CFS patients exhibited many significantly altered EV proteomic responses compared with controls, including downregulation of TCA cycle-related proteins and upregulation of complement system proteins at 15 min postexercise. Changes in proteins involved in protein folding and the endoplasmic reticulum (ER) stress response during recovery were highly correlated with PEM severity, highlighting their potential as therapeutic targets. EV protein changes postexercise were also associated with disease severity and unrefreshing sleep. Correlations between EV protein levels and the exercise parameters VO₂ peak and ventilatory anaerobic threshold were observed in controls but were absent in ME/CFS patients, suggesting disrupted EV-mediated physiological processes.

Conclusions: ME/CFS patients exhibit a maladaptive EV proteomic response to exercise, characterized by metabolic impairments, immune overactivation, and ER stress response dysregulation. These findings provide insight into the molecular basis of PEM and suggest promising targets for improving recovery and energy metabolism in ME/CFS.

Source: Glass KA, Giloteaux L, Zhang S, Hanson MR. Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome. Clin Transl Med. 2025 May;15(5):e70346. doi: 10.1002/ctm2.70346. PMID: 40465195; PMCID: PMC12135887. https://pmc.ncbi.nlm.nih.gov/articles/PMC12135887/ (Full text)

Truncal ataxia or disequilibrium is an unrecognised cause of orthostatic intolerance in patients with myalgic encephalomyelitis

Introduction:

Chronic fatigue syndrome (CFS) causes a marked reduction in the activities of daily living and impairs the quality of life. Recently, dysfunction of the central nervous system associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of CFS.1 Most patients with ME/CFS have orthostatic intolerance (OI) which is the primary factor restricting the daily functional capacity and in turn quality of life.2-4 OI is characterised by the inability to remain upright without severe signs and symptoms, such as hypotension, tachycardia, light-headedness, pallor, fatigue, weakness, dizziness, diminished concentration, tremulousness and nausea. Most symptoms of OI have been surmised to be related to reduced cerebral blood flow with or without impaired cerebral circulatory autoregulation, and the compensatory activation of the sympathetic nervous system.5, 6 Indeed, many patients have postural orthostatic tachycardia, delayed orthostatic hypotension and neurally mediated hypotension.4, 5, 7-9 Also many patients have low cardiac output in association with a small left ventricle.10-12 With further progression of the disease, patients may have even sitting intolerance and finally become bedridden.

Although static balance is an essential element for the performance of daily activities as well as postural stability, the possible relation between disequilibrium and OI has never been investigated. The possible role of static or truncal ataxia in the genesis of both orthostatic and sitting intolerance was examined in patients with ME.

Source: Miwa K, Inoue Y. Truncal ataxia or disequilibrium is an unrecognised cause of orthostatic intolerance in patients with myalgic encephalomyelitis. Int J Clin Pract. 2017 Jun;71(6). doi: 10.1111/ijcp.12967. PMID: 28613452. https://onlinelibrary.wiley.com/doi/10.1111/ijcp.12967 (Full text)

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex heterogeneous multiorgan disease that can have severe impact on individuals’ quality of life. Diagnosis of ME/CFS is based on symptom presentation, and a significant goal for the field is to establish meaningful subtypes. The heterogeneity in the literature suggests that individuals living with ME/CFS may suffer from overlapping but different underlying pathophysiological mechanisms.

We enrolled 40 participants with ME/CFS and 41 matched healthy control subjects at the Bragée Clinic in Sweden. We assessed plasma samples from both ME/CFS cases and control groups and cerebrospinal fluid (CSF) samples from individuals with ME/CFS.

We investigated dysregulated pathways and disease profiles through clinical questionnaires; multiplex analyses of cytokines, hormones, and matrix metalloproteinases; pathogen seroreactivity through peptide display bacteria libraries; and high-throughput microarray for autoantibodies. All samples used were from humans.

We show altered interaction patterns between circulating biological factors in plasma of ME/CFS participants. Our analysis of CSF from individuals with ME/CFS revealed different immunotypes of disease. We found 2 patient clusters based on matrix metalloproteinases profiles. The subgroups had similar clinical presentation but distinct pathogen exposure and CSF inflammatory profiles.

Our findings shed light on ME/CFS immune phenotypes and generate hypotheses for future research in disease pathogenesis and treatment development by exploring disease subgroups.

Source: Bastos VC, Greene KA, Tabachnikova A, Bhattacharjee B, Sjögren P, Bertilson B, Reifert J, Zhang M, Kamath K, Shon J, Gehlhausen JR, Guan L, VanElzakker M, Proal A, Bragée B, Iwasaki A. Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome. J Immunol. 2025 May 15:vkaf087. doi: 10.1093/jimmun/vkaf087. Epub ahead of print. PMID: 40373264. https://academic.oup.com/jimmunol/advance-article/doi/10.1093/jimmun/vkaf087/8133211 (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing

Abstract:

Rationale: There is substantial overlap of exertional symptoms in Long COVID (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) including intractable fatigue, post-exertional malaise (PEM), and orthostatic intolerance, but very little objective data liking the two. This study compares exercise pathophysiology in the two disorders and normal controls using invasive cardiopulmonary exercise testing (iCPET).

Methods: Between January 2019 and December 2024, 1,518 patients underwent a clinical iCPET at Brigham and Women’s Hospital. Exclusion criteria included morbid obesity (BMI>40 kg/m2), severe anemia ([Hb]<9.0 g/dL), elite athletes (peak VO2 (pVO2)>120% predicted), sub-maximum effort (RER<1.05), a primary pulmonary mechanical limit (VE @ AT/MVV>0.7), and comorbidities such as active/treated cancer, interstitial lung disease, or other respiratory related diseases. iCPET results from 438 ME/CFS patients, 73 LC patients, and 43 symptomatic but otherwise normal controls were analyzed. pV02, peak cardiac output (pQc), peak right atrial pressure (pRAP), peak systemic oxygen extraction (pSOE; Ca-vO2/[Hb]), and ventilatory inefficiency (VE/VCO2 slope) were compared among groups. Statistical significance was determined using Kruskal-Wallis tests for global comparisons, with post-hoc Dunn tests for pairwise group comparisons. Holm-Bonferroni adjustments were applied to control for multiple comparisons.

Results: LC and ME/CFS displayed reduced pVO2 % predicted compared to controls (LC: 78.4 ± 18%, ME/CFS: 78.1 ± 17%, Controls: 97.5 ± 10%, P≤0.0001). Reduced pQc % predicted was also observed compared to controls (LC: 91.1 ± 18%, ME/CFS: 96.3%, Controls: 101 ± 11%, P≤0.001). pRAP were significantly less compared to controls (LC: 1.1 ± 3.1 mmHg, ME/CFS: 1.3 ± 2.8 mmHg, Controls: 3.6 ± 3.4 mmHg, P≤0.001). Significant reductions in pSOE were seen for LC and ME/CFS (LC: 0.81 ± 0.1, ME/CFS: 0.81 ± 0.1, Controls, 0.91 ± 0.1, P≤0.0001). The only measure with no significant difference between disease and control was VE/VCO2 slope (LC: 31.4 ± 8.4, ME/CFS: 31.6 ± 6.9, Controls: 32.0 ± 6.7, P≥0.261). Most interestingly, no significant differences were seen between the two diseases for any of the analyzed measures (P≥0.245).

Conclusions: We report the largest cohort of ME/CFS and LC investigated with iCPET to date. ME/CFS and LC share symptomatic, reduced aerobic capacity at peak exercise, which is driven by preload insufficiency and impaired systemic O2 extraction, the latter compatible with peripheral left-to-right shunting and/or limb skeletal muscle dysfunction. These findings should drive future diagnostics and personalized medicine in both diseases. We hope these data inform the pending prospective NIH RECOVER iCPET study of LC.

Source: J. Squires, S. Palwayi, P. Li, W. Xiao, K. LeWine, S.W. Johnson, D. Felsenstein, A.B. Waxman, and D.M. Systrom. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing [abstract]. Am J Respir Crit Care Med 2025;211:A7881. https://www.atsjournals.org/doi/​10.1164/ajrccm.2025.211.Abstracts.A7881

Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort

Abstract:

Background: Shared symptoms and biological abnormalities between post-acute sequelae of SARS-CoV-2 infection (PASC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could suggest common pathophysiological bases and would support coordinated treatment efforts. Empirical studies comparing these syndromes are needed to better understand their commonalities and differences.

Methods: We analyzed electronic health record data from 6.5 million adult patients from the National COVID Cohort Collaborative. PASC and ME/CFS diagnostic groups were defined based on recorded diagnoses, and other recorded conditions within the two groups were used to train separate machine learning-driven computable phenotypes (CPs). The most predictive conditions for each CP were examined and compared, and the overlap of patients labeled by each CP was examined. Condition records from the diagnostic groups were also used to statistically derive condition clusters. Rates of subphenotypes based on these clusters were compared between PASC and ME/CFS groups.

Results: Approximately half of patients labeled by one CP are also labeled by the other. Dyspnea, fatigue, and cognitive impairment are the most-predictive conditions shared by both CPs, whereas other most-predictive conditions are specific to one CP. Recorded conditions separate into cardiopulmonary, neurological, and comorbidity clusters, with the cardiopulmonary cluster showing partial specificity for the PASC groups.

Conclusions: Data-driven approaches indicate substantial overlap in the condition records associated with PASC and ME/CFS diagnoses. Nevertheless, cardiopulmonary conditions are somewhat more commonly associated with PASC diagnosis, whereas other conditions, such as pain and sleep disturbances, are more associated with ME/CFS diagnosis. These findings suggest that symptom management approaches to these illnesses could overlap.

Source: Powers JP, McIntee TJ, Bhatia A, Madlock-Brown CR, Seltzer J, Sekar A, Jain N, Hornig M, Seibert E, Leese PJ, Haendel M, Moffitt R, Pfaff ER; N3C Consortium and RECOVER-EHR. Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort. Commun Med (Lond). 2025 Apr 11;5(1):109. doi: 10.1038/s43856-025-00827-5. PMID: 40210986. https://www.nature.com/articles/s43856-025-00827-5 (Full text)

Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available. Approximately 60% of patients develop ME/CFS following an acute infection.

Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype. Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity. While trained immunity is beneficial to combat infections, a disproportionate response may cause disease.

We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS. In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.

Source: Humer B, Dik WA, Versnel MA. Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review. Front Immunol. 2025 Mar 25;16:1483764. doi: 10.3389/fimmu.2025.1483764. PMID: 40201181; PMCID: PMC11975576. https://pmc.ncbi.nlm.nih.gov/articles/PMC11975576/ (Full text)

Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the etiology of these illnesses remains largely unknown. Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients.

The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases. Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterization of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unraveling the metabolic phenotypes associated with these complex diseases.

Emerging evidence suggests that ME/CFS, GWS, and FM are all characterized by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention.

Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.

Source: Davis L, Higgs M, Snaith A, Lodge TA, Strong J, Espejo-Oltra JA, Kujawski S, Zalewski P, Pretorius E, Hoerger M, Morten KJ. Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front Neurosci. 2025 Mar 10;19:1498981. doi: 10.3389/fnins.2025.1498981. PMID: 40129725; PMCID: PMC11931034. https://pmc.ncbi.nlm.nih.gov/articles/PMC11931034/ (Full text)

mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS

Abstract:

Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined.

In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. ‘mTORC1 Syndrome’ (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

Source: Bar-Tana J. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS. J Transl Med. 2025 Mar 10;23(1):297. doi: 10.1186/s12967-025-06220-z. PMID: 40059164. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06220-z (Full text)

Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS)

Abstract:

We proposed that cerebrospinal fluid would provide objective evidence for disrupted brain metabolism in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). The concept of postexertional malaise (PEM) with disabling symptom exacerbation after limited exertion that does not respond to rest is a diagnostic criterion for ME/CFS. We proposed that submaximal exercise provocation would cause additional metabolic perturbations.

The metabolomic and lipidomic constituents of cerebrospinal fluid from separate nonexercise and postexercise cohorts of ME/CFS and sedentary control subjects were contrasted using targeted mass spectrometry (Biocrates) and frequentist multivariate general linear regression analysis with diagnosis, exercise, gender, age and body mass index as independent variables. ME/CFS diagnosis was associated with elevated serine but reduced 5-methyltetrahydrofolate (5MTHF).

One carbon pathways were disrupted. Methylation of glycine led to elevated sarcosine but further methylation to dimethylglycine and choline was decreased. Creatine and purine intermediates were elevated. Transaconitate from the tricarboxylic acid cycle was elevated in ME/CFS along with essential aromatic amino acids, lysine, purine, pyrimidine and microbiome metabolites. Serine is a precursor of phospholipids and sphingomyelins that were also elevated in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls.

The findings differ from prior hypometabolic findings in ME/CFS plasma. The novel findings generate new hypotheses regarding serine-folate-glycine one carbon and serine-phospholipid metabolism, elevation of end products of catabolic pathways, shifts in folate, thiamine and other vitamins with exercise, and changes in sphingomyelins that may indicate myelin and white matter dysfunction in ME/CFS.

Source: Baraniuk JN. Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). Sci Rep. 2025 Mar 3;15(1):7381. doi: 10.1038/s41598-025-91324-1. PMID: 40025157. https://www.nature.com/articles/s41598-025-91324-1 (Full text)