Category: Exercise

Dysregulation of extracellular vesicle protein cargo in female ME/CFS cases and sedentary controls in response to maximal exercise

Abstract:

In healthy individuals, physical exercise improves cardiovascular health and muscle stre ngth, alleviates fatigue, and reduces risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance. We hypothesized that altered extracellular vesicle (EV) signaling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post-exertional malaise).

EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age- and BMI-matched female sedentary controls at three time points: before, 15 minutes, and 24 hours after a maximal cardiopulmonary exercise test. EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag-based (TMT) proteomics.

The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS. Differentially abundant proteins in ME/CFS patients vs. controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system, and brain signaling.

Source: Ludovic Giloteaux, Katherine A. Glass, Arnaud Germain, Sheng Zhang, Maureen R. Hanson. Dysregulation of extracellular vesicle protein cargo in female ME/CFS cases and sedentary controls in response to maximal exercise. bioRxiv 2023.08.28.555033; doi: https://doi.org/10.1101/2023.08.28.555033 https://www.biorxiv.org/content/10.1101/2023.08.28.555033v1.full (Full text)

Consequences of sarcolemma fatigue on maximal muscle strength production in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

  • Does force failure result from sarcolemma fatigue in Myalgic Encephalomyelitis patients?
  • Two groups of Myalgic Encephalomyelitis patients with or not M wave alterations were compared.
  • Maximal handgrip strength and M wave in forearm muscle were simultaneously measured.
  • Post-exercise changes in Maximal handgrip strength and M wave were positively correlated.
  • The post exercise sarcolemma fatigue measured could be the cause of muscle failure in these patients.

Background: Myalgic encephalomyelitis is an invalidating chronic disease often associated with exercise-induced alterations of muscle membrane excitability (M wave). No simultaneous measurements of maximal isometric force production and sarcolemma fatigue in the same muscle group have been previously reported. We hypothesized that M wave alterations could be partly responsible for the reduced muscle force present in this invalidating disease.

Methods: This retrospective study compared two groups of patients who presented (n = 30) or not (n = 28) alterations of M waves evoked by direct muscle stimulation during and after a cycling exercise bout. The maximal handgrip strength was measured before and after exercise, concomitantly with electromyogram recordings from flexor digitorum longus muscle. The patients also answered a questionnaire to identify eventual exacerbation of their clinical symptoms following the exercise test.

Findings: The M wave amplitude significantly decreased in muscles and the M wave duration significantly increased in the group of patients with M wave alterations after exercise. Resting values of handgrip were significantly lower in patients with exercise-induced M-wave alterations than in patients without M-wave abnormalities. In patients with exercise-induced M-wave alterations, handgrip significantly decreased after exercise and the changes in handgrip and M wave were positively correlated. The frequency of post-exertion malaise, increased fatigue, myalgia, headache and cognitive dysfunction was significantly higher in patients with M-wave alterations and variations in handgrip after exercise.

Interpretation: These data suggest that post-exercise sarcolemma fatigue often measured in patients with myalgic encephalomyelitis could be the cause of muscle failure.

Source: Frédérique Retornaz, Chloé Stavris, Yves Jammes. Consequences of sarcolemma fatigue on maximal muscle strength production in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Clinical Biomechanics, Volume 108, August 2023, 106055. https://www.sciencedirect.com/science/article/pii/S0268003323001869 (Full text)

Exercise Capacity and Vascular Function in Long-COVID Sufferers

Abstract:

Background: Exercise intolerance is a prominent aetiology of long-COVID syndrome, yet the mechanisms causing the debilitation remain unknown. Vascular dysfunction is thought to play a role, hence we sought to determine if there is a relationship between exercise capacity and vascular function in COVID survivors.

Methods: Forty-two COVID-19 survivors; 33 self-identified long-COVID sufferers and 9 recovered controls (40.7±11.8 vs 40.2±14.5 years, both 67% female) underwent extensive phenotyping >3 months post-infection. Blood pressure (BP) and heart rate were measured (automated BP device), before carotid, femoral, and radial tonometry (carotid–femoral pulse wave velocity; [cPWV], augmentation index; [AIx]) were performed to assess vascular stiffness. Endothelium-dependent and independent dilatation were assessed via brachial artery flow-mediated dilation ([FMD]; Doppler-ultrasound) in response to reactive hyperaemia and glyceryl trinitrate respectively. Cardiopulmonary exercise testing determined peak oxygen uptake (VO2).

Results: Long-COVID sufferers had reduced VO2 peak compared to controls (26.5±7.0 vs 32.8±11.3 ml/min/kg, p= 0.045). Haemodynamic and vascular function were similar between groups, though there was a medium effect size (ES) for between group differences in cPWV (6.6±1.2 vs 6.1±0.9 m/sec, p=0.20; ES 0.44) and AIx (14±15% vs 4±16%, p=0.11; ES 0.67). VO2 peak was inversely correlated with AIx (r = -0.60, p<0.001) and cPWV (r = -0.55, p<0.001). There was no significant association between endothelial function and exercise capacity parameters.

Conclusions: Lower VO2peak measures in long-COVID participants were strongly associated with increased AIx and cPWV. These findings indicate the need for further longitudinal investigations to determine if these manifestations persist and impact long-term cardiovascular health.

Source: I.Wallace, E. Howden, D. Green, G. Sesa-Ashton. Exercise Capacity and Vascular Function in Long-COVID Sufferers. Heart, Lung and Circulation. ABSTRACT| VOLUME 32, SUPPLEMENT 3, S114-S115, JULY 2023. https://www.heartlungcirc.org/article/S1443-9506(23)04000-3/fulltext 

Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM.
Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.
Source: Gamer J, Van Booven DJ, Zarnowski O, Arango S, Elias M, Kurian A, Joseph A, Perez M, Collado F, Klimas N, et al. Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project. International Journal of Molecular Sciences. 2023; 24(12):10255. https://doi.org/10.3390/ijms241210255 https://www.mdpi.com/1422-0067/24/12/10255 (Full text)

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

Abstract:

Background: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity.

Methods: We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.

Results: Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.

Conclusions: Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.

Source: Durstenfeld MS, Peluso MJ, Kaveti P, Hill C, Li D, Sander E, Swaminathan S, Arechiga VM, Lu S, Goldberg SA, Hoh R, Chenna A, Yee BC, Winslow JW, Petropoulos CJ, Kelly JD, Glidden DV, Henrich TJ, Martin JN, Lee YJ, Aras MA, Long CS, Grandis DJ, Deeks SG, Hsue PY. Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID. J Infect Dis. 2023 May 11:jiad131. doi: 10.1093/infdis/jiad131. Epub ahead of print. PMID: 37166076. https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad131/7159960 (Full text available as PDF file)

Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation

Abstract:

Abstract available online: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Source: S. Jothi, G. Claessen, M. Insel, S. Kubba, E. Howden, S.-R. Carmona, F.P. Rischard. Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing

Abstract

Introduction: Mechanisms underlying exercise and orthostatic intolerance in myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS) have been uncovered by invasive cardiopulmonary exercise testing (iCPET) and
autonomic function testing (AFT), but the relationships between the two are not known. This study aims to determine
if there is overlap of cardiovascular and respiratory pathophysiology in patients who have undergone both
tests.

Methods: Between January 2017 and April 2022, 62 patients were identified with a contemporary iCPET and
AFT. Key variables from the iCPET included peak oxygen uptake (pVO2), cardiac output (pQc), right atrial pressure
(pRAP), and systemic oxygen extraction (Ca-vOy/Hgb) at peak exercise. Key variables from the autonomic testing
included epidermal and sweat gland small fiber neurite density, electrochemical skin conductance, and change in
heart rate (AH) and end tidal carbon dioxide (AETCO2) from supine to upright during the tilt table test
(TTT).

Results: All 62 patients demonstrated preload failure (pRAP < 6.5mmHg). Of this group, 54 patients (87.1%) fulfilled NAM criteria for ME/CFS, with 32 testing positive (59.3%) for small fiber neuropathy (SFN) using either morphological and/or functional testing. Significant correlations were found between pVOg and both AH (r=-0.439. P<0.05) and AETCO, (r=0.474, P<0.05) during TTT. The same tilt table variables were found to be significantly correlated with pQc (r=-0.365, P<0.05 and r=0.351, P<0.05) from the iCPET. It should be noted that 8 of the ME/CFS SFN patients (25%) fulfilled diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) based on the tilt table test.

Conclusion: Decreased oxygen uptake and cardiac output at peak exercise during iCPET correlated with a greater change in heart rate and ETCO from supine to upright during TTT. There appears to be significant overlap of cardiopulmonary pathophysiology in ME/CFS underlying exercise and orthostatic symptoms.

Source: J. Squires, K. Wichmann Madsen, M.C. Stovall, S. Al-Zayer, W. Xiao, C.-J. Chang, P. Novak, D.M. Systrom. ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing. American Journal of Respiratory and Critical Care Medicine 2023;207:A2996. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2996

Sex Differences in Hemodynamic Response to Exercise in Patients With Myalgic Encephalomyelitis: Insights From Invasive Cardiopulmonary Exercise Testing

Abstract:

Abstract available online: https://www.atsjournals.org/doi/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2995

Source: K. Wichmann Madsen, J. Squires, M.C. Stovall, S. Al-Zayer, C.-J. Chang, W. Xiao, R. Pari, P. Joseph, D.M. Systrom. Sex Differences in Hemodynamic Response to Exercise in Patients With Myalgic Encephalomyelitis: Insights From Invasive Cardiopulmonary Exercise Testing. American Journal of Respiratory and Critical Care Medicine 2023;207:A2995 https://www.atsjournals.org/doi/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2995

A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background A central feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is post exertional malaise (PEM), which is an acute worsening of symptoms after a physical, emotional and/or mental exertion. PEM is also a feature of Long COVID. Dynamic measures of PEM have historically included scaled questionnaires which have not been validated in ME/CFS. To enhance our understanding of PEM and how best to measure it, we conducted semi-structured qualitative interviews (QIs) at the same intervals as Visual Analog Scale (VAS) measures after a Cardiopulmonary Exercise Test (CPET).

Methods Ten ME/CFS and nine healthy volunteers participated in a CPET. For each participant, PEM symptom VAS (7 symptoms) and semi-structured QIs were administered at six timepoints over 72 hours before and after a single CPET. QI data were used to plot the severity of PEM at each time point and identify the self-described most bothersome symptom for each patient. QI data were used to determine the symptom trajectory and peak of PEM. Performance of QI and VAS data were compared to each other using Spearman correlations.

Results QIs documented that each ME/CFS volunteer had a unique PEM experience, with differences noted in the onset, severity, trajectory over time, and most bothersome symptom. No healthy volunteers experienced PEM. Scaled QI data were able to identify PEM peaks and trajectories, even when VAS scales were unable to do so due to known ceiling and floor effects. QI and VAS fatigue data corresponded well prior to exercise (baseline, r=0.7) but poorly at peak PEM (r=0.28) and with the change from baseline to peak (r=0.20). When the most bothersome symptom identified from QIs was used, these correlations improved (r=.0.77, 0.42. and 0.54 respectively) and reduced the observed VAS scale ceiling and floor effects.

Conclusion QIs were able to capture changes in PEM severity and symptom quality over time in all the ME/CFS volunteers, even when VAS scales failed to do so. Information collected from QIs also improved the performance of VAS. Measurement of PEM can be improved by using a quantitative-qualitative mixed model approach.

Disclaimer This research/work/investigator was supported (in part) by the Division of Intramural Research of the National Institutes of Health, NINDS. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health.

Source: Barbara Stussman, Brice Calco, Gina Norato, Angelique Gavin, Snigdha Chigurupati, Avindra Nath, Brian Walitt. A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv 2023.04.24.23288821;  doi: https://doi.org/10.1101/2023.04.24.23288821 https://www.medrxiv.org/content/10.1101/2023.04.24.23288821v1.full-text (Full text)

Lung diffusing capacities for nitric oxide and carbon monoxide at rest and post-walking in long COVID

Abstract:

Background: Approximately one-third of long coronavirus disease 2019 (long COVID) patients report breathlessness and fatigue even during activities of daily living. We hypothesised that abnormalities of combined diffusing capacity of the lung for nitric oxide (D LNO) and carbon monoxide (D LCO) at rest or after mild exercise are associated with breathlessness in patients with long COVID.

Methods: Single-breath combined D LNO and D LCO were measured at rest and immediately after a short bout of treadmill exercise simulating ordinary walking in 32 Caucasian patients with long COVID and dyspnoea at rest. 20 subjects served as a control group.

Results: At rest, combined D LNO, D LCO and alveolar volume (V A) were significantly lower in long COVID than in controls, with D LNO and D LCO being below the limits of normal in 69% and 41% of cases, respectively. Mean values of D LNO/V A and D LCO/V A in long COVID patients were less than controls, yet, in only 22% and 12% of long COVID patients were the values of D LNO/V A and D LCO/V A below the limits of normal. After treadmill exercise, D LNO, D LNO/D LCO, V A and heart rate increased significantly without differences between groups. D LNO remained below the limit of normal in 47% of long COVID patients.

Conclusion: These data suggest localised discrete loss of lung units in approximately half of long COVID patients, not completely explained by loss of V A or of alveolar-capillary recruitment during exercise.

Source: Barisione G, Brusasco V. Lung diffusing capacities for nitric oxide and carbon monoxide at rest and post-walking in long COVID. ERJ Open Res. 2023 Apr 17;9(2):00363-2022. doi: 10.1183/23120541.00363-2022. PMID: 37070120; PMCID: PMC9638122. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638122/ (Full text)