Tag: exercise

Is the RACGP HANDI recommendation of incremental physical activity for chronic fatigue syndrome/myalgic encephalomyelitis harming patients?

Opinion:

In April 2024, The Royal Australian College of General Practitioners (RACGP) Handbook of Non-Drug Interventions (HANDI)committee published a guideline: Incremental physical activity for chronic fatigue syndrome/myalgic encephalomyelitis.1 The HANDI committee claims to recommend interventions that are based on ‘solid evidence’.2 But is this always the case?

An evaluation under the AGREE II instrument for assessing guidelines scored the RACGP guideline at only 2% for rigour of development.3 Alarmingly, the guideline provides no evidence of a systematic review of the literature, nor an analysis of the strengths and limitations of the three cited papers: the PACE trial; the Cochrane review, Exercise therapy for chronic fatigue syndrome; and Fawzy et al’s systematic review of treatments for post-acute COVID-19 syndrome [PACS]).1,4,5,6 Indeed, the PACE trial has been heavily criticised for outcome switching and bias.7–9 If the PACE trial had adhered to the original definition of recovery laid out at the beginning of the study, only 4% of graded exercise therapy participants would have been classified as recovered, and the effect would not have been statistically significant.9 After participants had completed therapy, the study’s authors weakened the definition of recovery to encompass values that fall far below healthy norms. In fact, many ‘recovered’ participants were still sick enough to meet the entry requirements to the study.8 Worse, some participants were classified as recovered or improved before undertaking any treatment.10

Read the rest of this article HERE>>

Source: Jacqueline Stallard Stephan Praet Sandeep Gupta Angela Smith. Is the RACGP HANDI recommendation of incremental physical activity for chronic fatigue syndrome/myalgic encephalomyelitis harming patients? AJGP, Viewpoint​
Volume 55, Issue 3, March 2026. https://www1.racgp.org.au/ajgp/2026/march/is-the-racgp-handi-recommendation-of-incremental-p (Full text)

Inefficient energy consumption is related to post exertional malaise during cardiopulmonary exercise testing in long COVID

Abstract:

Background: Dyspnea, fatigue and post-exertional malaise (PEM) are hallmark features of long Covid and emerging evidence suggests that abnormal energy metabolism may contribute to these symptoms. A cardiopulmonary exercise test (CPET) provides a detailed physiologic assessment of ventilatory and cardiovascular function and can offer insights into metabolic substrate utilization energy at rest and during exertion. Our aim was to evaluate patterns of energy metabolism at rest and during exercise during a CPET in patients with long Covid.

Methods: We conducted a cross-sectional study of consecutive non-selected patients that had been referred for a CPET. We included two groups: a long COVID and a control group. The CPET was performed on a cycle ergometer and we measured standard variables including oxygen uptake (V̇O₂), respiratory exchange ratio (RER), breathing reserve, heart rate, O2 pulse, and anaerobic threshold. We used RER to calculate indirect calorimetry estimating the use of carbohydrates and fat at rest and exertion. We analyzed the association between long COVID symptom severity symptoms including fatigue and post-exertional malaise (PEM) with patterns of energy consumption. We used logistic regression and area under the receiver operating characteristic curve to determine which CPET variables were most associated with long COVID.

Results: CPET results were analyzed for 50 patients who met the definition of long COVID and 45 patients controls. Long COVID patients and controls had similar peak V̇O₂, heart rate on exertion and V̇O₂ at anaerobic threshold. Seventy-three percent of patients with long COVID had predominant energy use of carbohydrates rather than fat at rest compared to 20% of controls. In multivariable models the odds ratio of using fat as energy source at rest was 0.99; 95% CI 0.99–0.99; p = 0.04. Patients with long COVID and severe fatigue as well as severe PEM had higher usage of carbohydrates (p < 0.01) and similar use of fat.

Conclusion: Patients with long COVID use energy inefficiently and this pattern could serve as a diagnostic feature in certain presentations of long COVID.

Source: Leonardo Tamariz, Brian Garnet, Santiago Avecillas et al. Inefficient energy consumption is related to post exertional malaise during cardiopulmonary exercise testing in long COVID, 15 December 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8072121/v1] https://www.researchsquare.com/article/rs-8072121/v1 (Full text)

Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion

Abstract:

The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan® 7K aptamer-based assay to monitor 6,361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-hour recovery period.

The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM.

Compared to controls, ME/CFS subjects showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls.

Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research.

Finally, our analysis of sedentary controls contributes new data of molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.

Source: Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Mol Cell Proteomics. 2025 Nov 12:101467. doi: 10.1016/j.mcpro.2025.101467. Epub ahead of print. PMID: 41237904. https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext (Full text)

Abnormal breathing patterns and hyperventilation are common in patients with chronic fatigue syndrome during exercise

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience symptoms of fatigue, dyspnea, mental fog, and worsening fatigue after physical or mental efforts. Some of these patients have been found to hyperventilate. In long COVID patients, many of whom also have ME/CFS, dysfunctional breathing (DB) has been described. Whether patients with ME/CFS, independent of COVID-19, experience dysfunctional breathing is unknown, as well as how it may relate to hyperventilation.

Methods: We performed serial 2-day cardiopulmonary exercise testing (CPET) in 57 patients with ME/CFS and 25 age- and activity-matched control participants. Peak oxygen consumption (VO2), ventilatory efficiency slope (VE/VCO2), O2 saturation, end-tidal CO2 (PetCO2), heart rate, and mean arterial blood pressure were measured in all patients during upright incremental bicycle exercise. Ventilatory patterns were reviewed using minute ventilation (VE) versus time, respiratory rate, and tidal volume versus minute ventilation graphs. Chronic hyperventilation (HV) was defined as a PETCO2 of <34 mm Hg that persisted during low-intensity exercise. Dysfunctional breathing was characterized by a 15% increase in oscillations in minute ventilation during at least 60% of the exercise duration or by a scatterplot pattern of respiratory rate and tidal volume plotted versus minute ventilation.

Results: The patients with ME/CFS had an average age of 38.6 ± 9.6 years, and a mean body mass index (BMI) of 24.1 ± 3.4, which was comparable to the sedentary controls. All participants performed maximal exercise, achieving a respiratory exchange ratio (RER) of >1.05. For the patients with ME/CFS, peak VO2 averaged 22.3 ± 5.3 mL/kg/min, which was 79 ± 20% of predicted and comparable to that observed in the sedentary controls (23.4 ± 4.6 mL/kg/min; 81 ± 12%; p = NS). A total of 24 patients with ME/CFS (42.1%) met the criteria for dysfunctional breathing compared to four sedentary controls (16%) (p < 0.02). In total, 18 patients with ME/CFS (32%) had hyperventilation compared to one sedentary control participant (4%) (p < 0.01), and nine patients with ME/CFS had both hyperventilation and dysfunctional breathing, whereas no sedentary participant exhibited both. The patients with ME/CFS and hyperventilation had significantly higher VE/VCO2 ratios (HV+: 34.7 ± 7.2; HV−: 28.1 ± 3.8; p < 0.001). A total of 15 of 18 patients with hyperventilation (83%) had either elevated VE /VCO2 ratios (n = 15) or dysfunctional breathing (n = 9) compared to 44% (n = 17) of the 40 non-hyperventilators (p < 0.01).

Conclusion: Dysfunctional breathing and hyperventilation are common in patients with ME/CFS and could present a new therapeutic target for these patients.

Source: Mancini Donna M. , Brunjes Danielle L. , Cook Dane , Soto Tiffany , Blate Michelle , Quan Patrick , Yamazaki Tadahiro , Norweg Anna , Natelson Benjamin H. Abnormal breathing patterns and hyperventilation are common in patients with chronic fatigue syndrome during exercise. Frontiers in Medicine, Volume 12 – 2025. DOI=10.3389/fmed.2025.1669036. ISSN=2296-858X https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1669036 (Full text)

Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19

Abstract:

Purpose: In individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC), physical activity can exacerbate symptoms for days-to-weeks, referred to as post-exertional symptom exacerbation (PESE). This study characterized the trajectory of PESE symptoms before and for 7 days after a sub-maximal exercise task in individuals with ME/CFS or PASC.

Methods: Individuals with ME/CFS (n=30) or PASC (n=30) and matched controls (n=30) were recruited from a university hospital and the community setting. Participants completed a 25-minute moderate intensity exercise on a whole-body cycle ergometer. The trajectory of 8 commonly reported PESE symptoms (physical fatigue, mental fatigue, pain, physical function, flu-like symptoms, gastrointestinal symptoms, sleep dysfunction, anxiety) before and for 7 days after exercise.

Results: There was variability in the proportion of those who experienced increased symptoms ranging from 46/60 reporting physical fatigue to only 18/30 reporting anxiety. There was no change in any of the symptoms across the 7-day period when analyzed individually. An aggregate score of 4-5 symptoms that includes physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, was more comprehensive in capturing maximal changes in PESE. Changes were greatest during the 72h post-exercise and for those with ME/CFS. The aggregate score shows 8/30 of individuals with ME/CFS and 12/30 with PASC show minimal-to-no increase in PESE, while 6-7/30 show increases greater than 3/10 points.

Conclusions: PESE to a clinically relevant exercise task is variable in individuals with ME/CFS and PASC as submaximal exercise does not exacerbate symptoms for some, while modifications of intensity may be necessary to minimize PESE in others.

Source: Berardi G, Janowski A, McNally S, Post A, Garg A, Sluka KA. Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19. Med Sci Sports Exerc. 2025 Nov 4. doi: 10.1249/MSS.0000000000003891. Epub ahead of print. PMID: 41185151. https://pubmed.ncbi.nlm.nih.gov/41185151/

Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome

Letter:

Response to B. Walitt et al. Nature Communications https://doi.org/10.1038/s41467-024-45107-3 (2024)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, systemic disease with significant pathophysiological uncertainties and variable presentations1. Here, we challenge Walitt et al.’s2 conclusion that post-infectious (PI) ME/CFS is a disorder defined by altered effort preference, leading to activity avoidance and subsequent deconditioning. We believe this interpretation risks reinforcing skepticism about the serious biological nature of ME/CFS and its hallmark of post-exertional malaise (PEM), as well as its potential misclassification as a mental health condition.

Walitt et al.2 utilized a single CPET to evaluate systems-level physiological responses to exercise. However, this methodology does not allow for measuring responses after an initial exertion, which is critically important for fully understanding PEM3. Over the past two decades, 2-day CPET has been used to characterize the systems-level metabolism of ME/CFS3. This paradigm uses an initial maximal CPET to establish the individual’s baseline performance and as a participant-referenced method to induce PEM4. A second maximal CPET is then conducted 24 h later to measure physiological and perceptual responses to exercise during the post-exertional state4. Standard objective criteria to evaluate effort are used to ensure maximal testing, including the respiratory exchange ratio at peak exertion4. This removes uncertainty related to effort. Meta-analyses involving participants with ME/CFS who have completed 2-day CPET indicate characteristic declines in the volume of oxygen consumed, work rate, and heart rate (HR) at submaximal exertion on the second CPET. These findings are reliably observed in people with ME/CFS but not deconditioned individuals5,6,7. Accordingly, the Institute of Medicine (IOM) cautioned that “a single CPET may be insufficient to document the abnormal response of ME/CFS patients to exercise.”1 (p. 106)

Using a single CPET introduces a threat to validity in Walitt et al.’s study2, as it did not allow for the measurement of submaximal performance decrement in the post-exertional state1,3,4,5,6. This is important because deconditioning and PEM are not mutually exclusive. Special care must be taken when applying and interpreting CPET results1. Failure to use 2-day CPET prevented the authors from adequately testing their conclusion that PEM is related to participants’ effort preference, as they did not evaluate physiological performance under conditions involving objective, standardized criteria for maximal exertion. Unfortunately, the use of a single CPET in this study contributed to the authors’ misinterpretation that PEM is synonymous with reduced effort and deconditioning.

Read the rest of this letter here: https://www.nature.com/articles/s41467-025-64538-0

Source: Davenport, T.E., Scheibenbogen, C., Zinn, M.A. et al. Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 16, 9176 (2025). https://doi.org/10.1038/s41467-025-64538-0 https://www.nature.com/articles/s41467-025-64538-0 (Full text)

Precision Medicine Study of Post-Exertional Malaise Epigenetic Changes in Myalgic Encephalomyelitis/Chronic Fatigue Patients During Exercise

Abstract:

Post-exertional malaise (PEM) is a defining symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its molecular underpinnings remain elusive. This study investigated the temporal-longitudinal DNA methylation changes associated with PEM using a structured two-day maximum repeated effort cardiopulmonary exercise testing (CPET) protocol involving pre- and two post-exercise blood samplings from five ME/CFS patients.

Cardiopulmonary measurements revealed complex heterogeneous profiles among the patients compared to typical healthy controls, and VO2 peak indicated all patients had poor normative fitness. The switch to anaerobic metabolism occurred at a lower workload in some patients on Day Two of the test. Reduced Representation Bisulphite Sequencing followed by analysis with Differential Methylation Analysis Package-version 2 (DMAP2) identified differentially methylated fragments (DMFs) present in the DNA genomes of all five ME/CFS patients through the exercise test compared with ‘before exercise’.

With further filtering for >10% methylation differences, there were early DMFs (0-24 h after first exercise test) and late DMFs between (24-48 h after the second exercise test), as well as DMFs that changed gradually (between 0 and 48 h). Of these, 98% were ME/CFS-specific, compared with the two healthy controls accompanying the longitudinal study. Principal component analysis illustrated the three distinct clusters at the 0 h, 24 h, and 48 h timepoints, but with heterogeneity among the patients within the clusters, highlighting dynamic methylation responses to exertion in individual patients.

There were 24 ME/CFS-specific DMFs at gene promoter fragments that revealed distinct patterns of temporal methylation across the timepoints. Functional enrichment of ME-specific DMFs revealed pathways involved in endothelial function, morphogenesis, inflammation, and immune regulation. These findings uncovered temporally dynamic epigenetic changes in stress/immune functions in ME/CFS during PEM and suggest molecular signatures with potential for diagnosis and of mechanistic significance.

Source: Sharma S, Hodges LD, Peppercorn K, Davis J, Edgar CD, Rodger EJ, Chatterjee A, Tate WP. Precision Medicine Study of Post-Exertional Malaise Epigenetic Changes in Myalgic Encephalomyelitis/Chronic Fatigue Patients During Exercise. Int J Mol Sci. 2025 Sep 3;26(17):8563. doi: 10.3390/ijms26178563. PMID: 40943482. https://www.mdpi.com/1422-0067/26/17/8563 (Full text)

Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC or “long COVID”) and chronic fatigue syndrome/myalgic encephalitis (CFS/ME) share symptoms such as exertional dyspnea. We used exercise oxygen pathway analysis, comprising six parameters of oxygen transport and utilization, to identify limiting mechanisms in both conditions. Invasive cardiopulmonary exercise testing was performed on 15 PASC patients, 11 CFS/ME patients, and 11 controls.

We evaluated the contributions of alveolar ventilation (V̇a), lung diffusion capacity (DL ), cardiac output (Q̇), skeletal muscle diffusion capacity (DM ), hemoglobin (Hb), and mitochondrial oxidative phosphorylation (Vmax) to peak oxygen consumption (V̇O2peak). To simulate targeted interventions, each variable was sequentially normalized to assess its impact on V̇O2peak. V̇O2peak was significantly reduced in both PASC and CFS/ME compared to controls.

Skeletal muscle O2 diffusion (DM ) was the most impaired parameter in both patient groups (p = 0.01). Correcting DM alone improved V̇O2 by 66% in PASC (p = 0.008) and 34.7% in CFS/ME (p = 0.06), suggesting a dominant role for peripheral O2 extraction in exercise limitation. Impaired skeletal muscle oxygen diffusion (DM ) is a shared mechanism of exercise intolerance in PASC and CFS/ME and may represent a therapeutic target. However, our findings are limited by small sample size.

Source: Jothi S, Insel M, Claessen G, Kubba S, Howden EJ, Ruiz-Carmona S, Levine T, Rischard FP. Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation. Physiol Rep. 2025 Sep;13(17):e70535. doi: 10.14814/phy2.70535. PMID: 40892700. https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.70535 (Full text)

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise.

We report evidence of an exaggerated innate immune response after exposures to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked with lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways and dysregulation of the tryptophan-serotonin-kynurenine pathways.

Many of these underlying abnormalities worsened following exercise in ME/CFS patients, but not in healthy subjects; many abnormalities reinforced each other and several were correlated with the intensity of symptoms. Our findings may inform targeted therapeutic interventions for ME/CFS and PEM.

Source: Che X, Ranjan A, Guo C, Zhang K, Goldsmith R, Levine S, Moneghetti KJ, Zhai Y, Ge L, Mishra N, Hornig M, Bateman L, Klimas NG, Montoya JG, Peterson DL, Klein SL, Fiehn O, Komaroff AL, Lipkin WI. Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. medRxiv [Preprint]. 2025 Jul 24:2025.07.23.25332049. doi: 10.1101/2025.07.23.25332049. PMID: 40778181; PMCID: PMC12330418. https://pmc.ncbi.nlm.nih.gov/articles/PMC12330418/ (Full text available as PDF file)

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)