Tag: exercise

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)

Multimodal Web-Based Telerehabilitation for Patients With Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial

Abstract:

Background: Patients with post-COVID-19 condition (PCC) experience persistent, long-term health consequences following SARS-CoV-2 infection, including fatigue, hyperventilation, cognitive impairment, and limitations in daily activities. There is emerging evidence suggesting that exercise and respiratory therapy-based telerehabilitation is safe and could potentially improve physical capacity while reducing health care costs.

Objective: This study aims to evaluate the superiority of a multimodal, symptom-titrated telerehabilitation program over standard care in patients with PCC who are severely affected, using the highest oxygen uptake rate (VO2peak [mL/min/kg]) achieved during the cardiopulmonary exercise test (CPET) and minute ventilation/carbon dioxide production slope (VE/VCO2 [full slope]) as primary outcomes. In addition, this study seeks to provide novel insights into the clinical and physiological adaptations associated with PCC, informing future rehabilitation strategies.

Methods: This prospective, randomized, waitlist-controlled trial was approved by the Rhineland-Palatinate Medical Association ethics committee. All procedures comply with the Declaration of Helsinki. This study comprises 3 examination time points, which include patient-reported outcomes, clinical assessments, and a CPET. It is structured into an 8-week intervention phase followed by an 8-week follow-up phase. Following baseline assessment, patients will be randomly assigned to either the intervention group (IG) or the control group (CG). During the intervention phase, IG participants will receive a web-based, multimodal, symptom-titrated telerehabilitation program consisting of sports medicine consultations, weekly teleconsultations, a structured pacing approach, and exercise and respiratory therapy. In contrast, CG participants will receive treatment as usual, which includes a single sports medicine consultation on healthy habits and a self-directed pacing approach for managing symptoms and daily activities. During the follow-up phase, IG participants will continue training independently without teleconsultations, whereas CG participants will undergo the same telerehabilitation intervention as the IG. A follow-up assessment will be conducted for both groups to evaluate long-term effects. This study adheres to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines and follows the Consensus on Exercise Reporting Template.

Results: Recruitment began in August 2023 and was extended until March 2025. As of March 2025, 80 participants have been recruited, and data analysis is ongoing. Final results are expected by December 2025, with a cross-sectional analysis of baseline data anticipated by July 2025.

Conclusions: This study is the first randomized controlled trial investigating the effectiveness of multimodal and symptom-titrated telerehabilitation in patients with PCC who are severely affected. The integration of various objective diagnostic systems will provide valuable insights into emerging postviral fatigue syndromes, supporting the development of CPET-based diagnostics, personalized rehabilitation strategies, and future research on long-term telerehabilitation effectiveness. The findings will be disseminated through peer-reviewed publications, professional networks, and patient advocacy groups to ensure scientific, clinical, and public impact.

Trial registration: German Clinical Trials Register (DRKS) DRKS00032394; https://drks.de/search/de/trial/DRKS00032394.

Source: Tomaskovic A, Weber V, Ochmann DT, Neuberger EW, Lachtermann E, Brahmer A, Haller N, Hillen B, Enders K, Eggert V, Zeier P, Lieb K, Simon P. Multimodal Web-Based Telerehabilitation for Patients With Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial. JMIR Res Protoc. 2025 May 21;14:e65044. doi: 10.2196/65044. PMID: 40397936. https://www.researchprotocols.org/2025/1/e65044 (Full text)

Stress-Induced Changes in Immune Signatures in ME/CFS Patients Determined by Transcriptome Analysis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM). We evaluated transcriptomic changes in peripheral blood mononuclear cells (PBMC) of ME/CFS patients undergoing an exercise challenge and explored the transcriptomic response to exercise and recovery in PBMC of ME/CFS patients, as compared to healthy controls using RNA sequencing technology. As transcriptomic changes in ME/CFS patients are still in the phase of discovery, analysis of data has to be stringent, and the most important results have to be validated by a different technology, such as real-time PCR or NanoString.

Source: Gamer J, Van Booven D, Zarnowski O, Perez M, Frank J, Pangeni RP, Collado F, Klimas NG, Oltra E, Nathanson L. Stress-Induced Changes in Immune Signatures in ME/CFS Patients Determined by Transcriptome Analysis. Methods Mol Biol. 2025;2920:103-112. doi: 10.1007/978-1-0716-4498-0_7. PMID: 40372680. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_7

Repeated Cardiopulmonary Exercise Testing of ME/CFS Patients

Abstract:

Post-exertional malaise is a cardinal symptom present in 95% of individuals with myalgic encephalomyelitis (ME/CFS). Repeated cardiopulmonary exercise testing has been momentous in revealing that the physiological systems of those with ME/CFS are impaired or damaged and do not respond to exercise/physical activity like those without the condition. The 24-h repeated exercise test may demonstrate a reduction in peak oxygen consumption (VO2 peak), VO2 at ventilatory threshold, power output at both peak and ventilatory threshold, along with a reduction/diminished maximal heart rate commensurate with chronotropic intolerance. In this chapter, I describe the process and methods of repeated cardiopulmonary exercise testing, used to assess exercise tolerance in individuals with ME/CFS.

Source: Hodges L. Repeated Cardiopulmonary Exercise Testing of ME/CFS Patients. Methods Mol Biol. 2025;2920:163-172. doi: 10.1007/978-1-0716-4498-0_10. PMID: 40372683. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_10

Measuring Biomarkers of Oxidative Stress in ME/CFS Patients

Abstract:

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have a deficiency in energy production as a result of dysfunctions in their mitochondrial metabolism, defects in the complexes of the electron transport chain, and in the regulation of reactive oxygen species (ROS). This can lead to an imbalance and excess of these species with subsequent modifications of proteins, lipids, and DNA.

Oxidative stress is defined as an accumulation of ROS due to a loss of regulation and the subsequent inability to detoxify them. The modifications to the cellular macromolecules by ROS can be used as biomarkers of oxidative stress and so have the potential to monitor the disease course of a condition like ME/CFS.

Proteins are especially vulnerable to oxidative stress as amino acid residues are naturally modified as part of cell signaling so, in an imbalance between ROS and antioxidants, proteins become modified at multiple sites potentially altering structure and function. Protein carbonyl modifications are stable and can be measured using 2,4-dinitrophenylhydrazine using a commercial ELISA assay. This has been applied here to immune cell proteins and plasma from ME/CFS patients who had moderate functional activity before and during an exercise protocol, and was shown to have potential as a marker of oxidative stress in these patients. The methods used to measure the DNA modification, 8-hydroxy-2′-deoxyguanosine (8-OHdG) are known to give varied results depending on the technology used.

Here, a commercial ELISA assay did not have the sensitivity to detect the modifications in the DNA before and during the exercise protocol of these ME/CFS patients.

Source: Walker M. Measuring Biomarkers of Oxidative Stress in ME/CFS Patients. Methods Mol Biol. 2025;2920:225-244. doi: 10.1007/978-1-0716-4498-0_13. PMID: 40372686. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_13

Post-exertional malaise in Long COVID: subjective reporting versus objective assessment

Abstract:

Background: Post-exertional malaise (PEM) is a central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive, and studies of the impact of exercise have yielded contradictory results.

Objective: The objective of this study was to examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor. Secondarily, Long COVID symptom responses to exercise were compared to those of ME/CFS and healthy volunteers.

Methods: Data from three registered clinical trials comprised four cohorts in this study: Long COVID Questionnaire Cohort (QC; n = 244), Long COVID Exercise Cohort (EC; n = 34), ME/CFS cohort (n = 9), and healthy volunteers (HV; n = 9). All cohorts completed questionnaires related to physical function, fatigue, and/or PEM symptoms. EC also performed a standardized exercise test (cardiopulmonary exercise test, CPET), and the PEM response to CPET was assessed using visual analog scales and qualitative interviews (QIs) administered serially over 72 h. EC PEM measures were compared to ME/CFS and HV cohorts. A secondary analysis of QI explored positive responses to CPET among EC, ME/CFS and HV.

Results: Self-reported PEM was 67% in QC and estimated at 27% in EC. Only 2 of 34 EC patients (5.9%) were observed to develop PEM after a CPET. In addition, PEM responses after CPET in Long COVID were not as severe and prolonged as those assessed in ME/CFS. Twenty-two of 34 EC patients (64.7%) expressed at least one of 7 positive themes after the CPET.

Conclusion: Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.

Source: Stussman B, Camarillo N, McCrossin G, Stockman M, Norato G, Vetter CS, Ferrufino A, Adedamola A, Grayson N, Nath A, Chan L, Walitt B, Chin LMK. Post-exertional malaise in Long COVID: subjective reporting versus objective assessment. Front Neurol. 2025 Apr 23;16:1534352. doi: 10.3389/fneur.2025.1534352. PMID: 40337174; PMCID: PMC12055772. https://pmc.ncbi.nlm.nih.gov/articles/PMC12055772/ (Full text)

Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID

Abstract:

Objectives Patients with Long COVID experience disabling fatigue, autonomic dysfunction, reduced exercise capacity, and post-exertional malaise (PEM). Heart rate variability (HRV) can evaluate autonomic function and monitor overexertion, potentially helping to mitigate PEM. This study aimed to use continuous multi-day HRV recordings to monitor overexertion and study autonomic function in Long COVID.

Method Heart rate and HRV were continuously measured in 127 patients with long COVID (43±11 years, 32% male) and 21 healthy controls (42±13 years, 48% male), and daily life activities tracked in a logbook. Participants underwent a (sub)maximal cardiopulmonary exercise test to determine heart rate at the first ventilatory threshold (VT1) to study HRV responses to exercise at different intensities.

Results HRV was lower in patients with long COVID compared to healthy controls during various daily activities and sleep (p<0.027). HRV remained lower for 24 hours after exercise below, at or above VT1 in patients, but not in healthy controls (p=0.010). Nighttime HRV decreased with intense exercise and longer durations in patients with long COVID (p=0.018), indicative of exercise-induced diurnal disturbances of the autonomic nervous system in long COVID.

Conclusion Heart rate variability, assessed by wearables, confirms autonomic dysfunction in patients with long COVID. The delayed recovery of the sympathovagal balance after exercise close and above to VT1 suggests that VT1 can be practically interpreted as a PEM threshold.

Application These results confirm the applicability of wearables to assess autonomic function and manage overexertion in long COVID patients.

What is already known on this topic Patients with long COVID often experience fatigue, autonomic dysfunction, and post-exertional malaise (PEM). HRV can be used as a non-invasive tool to measure autonomic function and recovery. Anecdotal evidence suggests lower HRV in patients with long COVID, but measurements are usually very short.

What this study adds This study demonstrates that continuous HRV monitoring through wearables can effectively identify overexertion and autonomic dysfunction during daily activities in patients with long COVID. Patients with long COVID have a lower heart rate variability during sleep and HRV remained significantly lower for a longer period after moderate-to-heavy exercise, that is generally associated with the induction of post-exertional malaise.

How this study might affect research, practice, or policy This study supports the use of wearables for assessing autonomic function and overexertion in daily life, helping patients with long COVID in pacing daily activities to mitigate symptoms of post-exertional malaise. HRV tracking after exercise shows that VT1 is a potential threshold for PEM. Sports physicians and physiotherapists can incorporate HRV biofeedback measures into pacing advice to patients. Additional research is needed to further investigate the effect of such an intervention.

Source: Twan Ruijgt, Anouk Slaghekke, Anneke Ellens, Kasper W. Janssen, Rob C.I. Wüst.. Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID. medRxiv 2025.03.18.25320115; doi: https://doi.org/10.1101/2025.03.18.25320115 https://www.medrxiv.org/content/10.1101/2025.03.18.25320115v1.full-text (Full text)

Physical function and psychosocial outcomes after a 6-month self-paced aquatic exercise program for individuals with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Purpose: A randomized-controlled trial to investigate the efficacy of a 6-month self-paced aquatic exercise intervention on physical function, symptoms and psychosocial measures in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Methods: Thirty-two individuals diagnosed with ME/CFS (55.0 ± 13.9 yr) were randomized into an intervention group (INT, n = 17) or control group (CON, n = 15) for a 6-month trial of two 20-min sessions per week of self-paced aquatic movements and stretches. Pre- and post-intervention outcomes included physiological measures, 6-min walk test, hand-grip strength, Sit-to-Stand, Apley’s shoulder test, Sit-Reach test, perceived exertion, fatigue (FACIT), anxiety/depression (HADS) questionnaires, and tiredness and pain scores (VAS 0-10 scale).

Results: The INT group significantly increased walk test distance (13.7%, P < 0.001), Sit-to-Stand scores (33.7%, P < 0.001) and peak expiratory pulmonary flow (12.9%, P = 0.028) post-intervention. Fatigue (29.5%, P = 0.005), depression (21.7%, P = 0.010), combined anxiety/depression scores (16.9%, P = 0.047) and resting diastolic blood pressure (4.8%, P < 0.001) also significantly improved for the INT group. Sit-Reach scores were significantly lower for the INT group compared to CON post-intervention (- 4.0 ± 10.4 vs + 4.3 ± 10.7 cm, P = 0.034). There were no adverse events or worsening of symptoms during the trial.

Conclusions: Self-paced, low-moderate-intensity aquatic exercise improved walk distance, lower limb strength, fatigue, depression and peak expiratory flow without worsening ME/CFS symptoms. This mode of low-intensity physical activity may confer mental health and physical benefits provided the activity is self-paced and within patient energy limits.

Source: Broadbent S, Coetzee S, Calder A, Beavers R. Physical function and psychosocial outcomes after a 6-month self-paced aquatic exercise program for individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Eur J Appl Physiol. 2025 Apr 5. doi: 10.1007/s00421-025-05759-5. Epub ahead of print. PMID: 40186656. https://link.springer.com/article/10.1007/s00421-025-05759-5 (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)

CBT and graded exercise therapy studies have proven that ME/CFS and long COVID are physical diseases, yet no one is aware of that

Introduction:

The cognitive behavioral model (CBmodel) (Surawy et al., ; Vercoulen et al., ) has dominated the world of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) since the 1990s. According to this model, a belief in an organic illness, known as dysfunctional beliefs, stops ME/CFS patients engaging in normal activities, resulting in avoidance behavior and deconditioning. The deconditioning then leads to further avoidance behavior and more deconditioning. According to the CBmodel, symptoms of ME/CFS are caused by deconditioning and not by an underlying illness.

Cognitive behavioral therapy with graded activity (CBTplus) and graded exercise therapy (GET) were designed to reverse the dysfunctional beliefs, the avoidance behavior and the deconditioning and lead to recovery. However, an extensive review of the literature found that CBTplus and GET do not restore the ability to work (Vink and Vink-Niese, ). Additionally, there are now many papers documenting complex disruptions to the body’s physiology in ME/CFS, particularly involving immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in the cellular energy production and the gene expression (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, ; Liu et al., ; Missailidis et al., ).

Source: Vink M, Vink-Niese A. CBT and graded exercise therapy studies have proven that ME/CFS and long COVID are physical diseases, yet no one is aware of that. Front Hum Neurosci. 2025 Jan 29;19:1495050. doi: 10.3389/fnhum.2025.1495050. PMID: 39944089; PMCID: PMC11814198. https://pmc.ncbi.nlm.nih.gov/articles/PMC11814198/ (Full text)