Category: Exercise

Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Post-exertional malaise (PEM) is a hallmark symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We monitored the evolution of 1,157 plasma metabolites in 60 ME/CFS cases (45 females, 15 males) and in 45 matched healthy control subjects (30 females, 15 males) before and after two maximal Cardiopulmonary Exercise Test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four timepoints allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of ME/CFS cases compared to the healthy control group.

Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid- as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions.

The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component to the homeostasis of many organs in the body, including the brain.

Source: Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. JCI Insight. 2022 Mar 31:e157621. doi: 10.1172/jci.insight.157621. Epub ahead of print. PMID: 35358096. https://pubmed.ncbi.nlm.nih.gov/35358096/

Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study

Abstract:

Background: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.

Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.

Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges’ g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).

Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).

Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.

Source: Cook DB, VanRiper S, Dougherty RJ, Lindheimer JB, Falvo MJ, Chen Y, Lin JS, Unger ER; MCAM Study Group. Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study. PLoS One. 2022 Mar 15;17(3):e0265315. doi: 10.1371/journal.pone.0265315. PMID: 35290404; PMCID: PMC8923458. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923458/  (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation

The physiology underlying postexertional symptom exacerbation (PESE) is abnormal in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and likely long COVID. Activity pacing approaches appear warranted to accommodate the unusual physiological deficits of PESE.

The Rationale for Heart Rate Monitoring

Similar to people living with ME/CFS,7 people living with long COVID have reported finding activity pacing to be helpful. This idea is reflected in current safe rehabilitation guidelines for this condition.8 PESE is challenging to self-manage because of the variability in onset, duration, and nature from person to person.2,6 Social stigma associated with PESE may lead people to overexert to meet the demands of their daily tasks. This stigma may be exacerbated by people telling patients that “it’s all in their head” or they “just need to exercise.” Variability and stigma, in turn, make it difficult to identify important activity triggers in the early stages of learning to manage PESE.

PESE is characterized by aerobic system dysfunction. Pacing based on heart rate can help the patient avoid the dysfunctional aerobic system by keeping their activity intensity at a level anaerobic metabolism will dominate. Heart rate monitoring (HRM) provides an element of predictive potential for the patient to understand when their activities exceed physiological limits and eventually may result in PESE. In this post, we will discuss activity pacing to manage PESE that is based on HRM.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation. Published online on February 23, 2022. https://doi.org/10.2519/jospt.blog.20220223 (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation

In a previous post, we demonstrated that the symptoms and physiology of postexertional symptom exacerbation (PESE) are inconsistent with deconditioning. PESE worsens in response to exercise and demonstrates a variable clinical presentation. We will build a clinical rationale for energy system first aid as a place to start helping people with PESE.

Graded Exercise May Be Harmful to People With PESE

It is not surprising that patients with PESE frequently report worsening symptoms and function with exercise prescribed based on time and activity quotas,1 based on the physiological evidence. The United Kingdom’s Pacing, graded Activity, and Cognitive behaviour therapy, a randomized Evaluation (UK PACE) compared the clinical outcomes of specialist medical care, adaptive pacing, and graded exercise therapy (GET) in 641 people with idiopathic, disabling fatigue.9 In this study, GET was a quota-based progressive exercise program, where subjects incrementally increased exercise regardless of symptoms. PESE was not a specific recruitment criterion for this trial.8,9 The trial did not adhere to the published protocol, without appropriate justification. The raw data was independently reanalyzed according to the original protocol,10 Upon reanalysis, most symptomatic and functional outcome findings from the UK PACE trial did not reach thresholds for clinical relevance. Many ME/CFS experts contend the results of GET are marginal, probably not clinically relevant or beneficial.10

Despite the important concerns of the UK PACE trial, the trial continues to exert outsized influence on clinical guidelines.3 Some countries’ systems developed formal treatment pathways based on flawed results. Treatment pathways involving GET may have exposed an untold number of patients with ME/CFS worldwide to a GET program that, at best, is marginally effective, and at worst, may be harmful. Recent clinical guidelines for people with PESE, such as long COVID, no longer involve GET.6,7 These omissions reflect the ongoing re-evaluation of how clinical care should proceed for people with PESE, including people with long COVID. Implicit to this re-evaluation is a further reflection on the generally accepted idea that “movement is medicine” in a way that universally benefits clinical populations.

Read the full article HERE.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation. JOSPT blog, Published online on February 16, 2022. https://doi.org/10.2519/jospt.blog.20220216 (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation

In a previous post on the JOSPT Blog, we outlined the connection between postacute sequalae to novel coronavirus (long COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through their common clinical presentation: postexertional symptom exacerbation (PESE). PESE suggests the presence of abnormal physiological responses to exercise/activity. These physiological responses may be measured using cardiopulmonary exercise testing (CPET), which allows for careful characterization of cardiac, pulmonary, and metabolic functioning during exercise. We will review the characteristic findings on CPET in people with PESE.

The Physiology of PESE

One well-established protocol involves consecutive-day CPETs.8 In deconditioned people and people with a whole host of health conditions, CPET measurements demonstrate low error variance. Yet, CPET measurements are known to vary between tests in people with PESE.2 The observed variation in people with PESE reflects the biological variance associated with PESE.2 Clues about biological variance can provide important information about the underlying pathoetiology, severity, and functional limitations present.2,8 CPET data from peak exertion and ventilatory anaerobic threshold (VAT) provide important snapshots of physiological functioning. Data from peak exertion tells us about the physiology of a person’s “top-end” performance, and data from VAT elucidates the physiology of more “everyday” levels of exertion.

Read the rest of this article HERE.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation. JOSPT blog, Published online on February 9, 2022. https://doi.org/10.2519/jospt.blog.20220209 (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity

Prolonged symptoms after infection with the novel coronavirus 2019 (SARS-COV-2) are an emerging challenge to individual patients, society, and clinicians. In a previous post on the JOSPT Blog, we identified several lessons from research and clinical practice in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that are important lessons for long COVID. The purpose of this post is to discuss the phenomenon of postexertional symptom exacerbation (PESE) and its clinical identification to recognize the potential onset of long COVID.

Data from a large international web-based patient survey indicate substantial symptom overlap between postacute SARS-COV-2 infection (long COVID) and ME/CFS at 6 months following the onset of first symptoms. Three quarters of respondents noted disabling fatigue and over half noted cognitive dysfunction.4 A unique finding of this survey was that 75% of respondents noted PESE, which is a worsening of symptoms after activity/exercise.4 PESE is foundational to the diagnosis of ME/CFS and it is common with long COVID.4,5 This observation suggests we can further extend lessons from ME/CFS to develop our understanding of long COVID.

Read the rest of this article HERE.

Source: Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity. Published online on February 2, 2022 https://doi.org/10.2519/jospt.blog.20220202

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.

Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.

Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.

Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.

Source: Rayhan RU, Baraniuk JN. Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Neurosci. 2021 Dec 15;15:748426. doi: 10.3389/fnins.2021.748426. PMID: 34975370; PMCID: PMC8714840. https://www.frontiersin.org/articles/10.3389/fnins.2021.748426/full  (Full text)

Markers of Cardiac Autonomic Function During Consecutive Day Peak Exercise Tests in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have been shown to exhibit altered ventilatory characteristics on the second of two progressive maximal cardiopulmonary exercise tests (CPET) performed on consecutive days. However, maximal exercise can exacerbate symptoms for ME/CFS patients and cause significant post-exertional malaise. Assessment of heart rate (HR) parameters known to track post-exertional fatigue may represent more effective physiological markers of the condition and could potentially negate the need for maximal exercise testing.

Sixteen ME/CFS patients and 10 healthy controls underwent a sub-maximal warm-up followed by CPET on two consecutive days. Ventilation, ratings of perceived exertion, work rate (WR) and HR parameters were assessed throughout on both days. During sub-maximal warm-up, a time effect was identified for the ratio of low frequency to high frequency power of HR variability (p=0.02) during sub-maximal warm-up, and for HR at ventilatory threshold (p=0.03), with both being higher on Day Two of testing. A significant group (p<0.01) effect was identified for a lower post-exercise HR recovery (HRR) in ME/CFS patients. Receiver operator characteristic curve analysis of HRR revealed an area under the curve of 74.8% (p=0.02) on Day One of testing, with a HRR of 34.5bpm maximising sensitivity (63%) and specificity (40%) suggesting while HRR values are altered in ME/CFS patients, low sensitivity and specificity limit its potential usefulness as a biomarker of the condition.

Source: Nelson MJ, Buckley JD, Thomson RL, Bellenger CR, Davison K. Markers of Cardiac Autonomic Function During Consecutive Day Peak Exercise Tests in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Physiol. 2021 Dec 14;12:771899. doi: 10.3389/fphys.2021.771899. PMID: 34970156; PMCID: PMC8713453.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713453/ (Full text)

Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Although autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people.

Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS.

This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.

Source: Van Oosterwijck J, Marusic U, De Wandele I, Meeus M, Paul L, Lambrecht L, Moorkens G, Danneels L, Nijs J. Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2021 Sep 30;10(19):4527. doi: 10.3390/jcm10194527. PMID: 34640544; PMCID: PMC8509376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509376/ (Full text)

The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome (CFS)

Abstract:

CFS is characterized by profound levels of persistent/recurrent fatigue. It is proposed that chronic, low level inflammation may play a role in this fatigue. We recruited 100 untreated patients with CFS (average age 33±12) and 100 age and sex matched healthy controls (HCs). Serum levels of TNF-α were assessed using ELISA. Subjective fatigue was determined by questionnaire and muscle function tests were undertaken in subgroups in which maximal voluntary contraction (MVC), electrically stimulated muscle force generation and rate of fatigue were assessed in the quadriceps muscle.

Subjective fatigue was higher in patients with CFS compared with HCs. Preliminary analyses showed that serum TNF-α was undetectable in 97% of HCs, whereas 15% of patients with CFS had detectable (4.4+/-0.18pg/ml) serum TNF-α. MVC was significantly reduced in subjects with CFS compared with HCs. No difference was seen in stimulated muscle fatigue between groups.

This preliminary data suggests that a sub-group of patients with CFS may have low level inflammation and analyses are underway to further characterise other inflammatory markers in serum and muscle of these patients and to determine whether such changes could affect indices of muscle function or central fatigue.

Funded by MRC, BBSRC and the ME Association.

Source: Earl, K., Sakellariou, G., Owens, D., Sinclair, M., Fenech, M., Close, G., Lawton, C., Dye, L., Beadsworth, M. and McArdle, A. (2015), The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome (CFS). The FASEB Journal, 29: 1055.34. https://doi.org/10.1096/fasebj.29.1_supplement.1055.34  https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.29.1_supplement.1055.34 (Full text)