Category: Exercise

Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology

Abstract:

The SARS-CoV-2 viral outbreak in 2020 resulted in a record number of global hospitalizations and deaths. Although most people recover from an initial COVID infection within 3 months, around 10% of people have symptoms that do not improve after 3 months, which is called long COVID. Other viruses and bacterial infections can also result in long-term symptoms, which is known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

One of the most common symptoms of long COVID or ME/CFS is post-exertional malaise, which is the worsening of symptoms or development of new symptoms after physical, mental or emotional stress. This can lead to patients leading less physically active lifestyles. Physical activity is known to be beneficial for overall health and wellbeing, mostly by increasing exercise capacity, which is a significant predictor in long-term health. Physical inactivity.

It is thought that many symptoms of long COVID and ME/CFS can be explained by lower physical activity of patients. However, people who are less physically active don’t experience post-exertional malaise, implying there are disease-specific changes. Many of the benefits that come from exercise come from a persons ability to adapt to an exercise session. Usually, exercise will create a short energy deficit, which then may result in small amounts of muscle damage. This then triggers a short-lived immune response, led first by neutrophils and macrophages, which result in activation of fibroadipogenic progenitor cells (FAP cells) and satellite cells (muscle stem cells). FAP cells and satellite cells communicate to repair damage to the muscle itself, while immune cells clear debris surrounding the muscle. In healthy situations, this creates a stronger, more resilient muscle. It is unknown whether these responses are still seen in long COVID or ME/CFS. The goal of this thesis then to 1) understand muscle changes in patients with long COVID and ME/CFS, 2) to better understand how these changes may relate to PEM, 3) to understand whether the muscle changes in patients are a result of physical inactivity.

Within the thesis, I find that patients with long COVID and ME/CFS have specific patterns of skeletal muscle that separate them from healthy individuals. This is highlighted by more fast-twitch fibre types, slow-twitch muscle atrophy, lower mitochondrial respiration that is separate from just mitochondrial loss, less metabolites related to oxidative capacity and antioxidation, less lipids that are required for cell membrane maintenance, and lower amounts of satellite cells and FAP cells.

Beyond this, I find that ME/CFS can be distinguished from long COVID by less capillaries, less slow-twitch fibres, less local immune cells, and lower amounts of several essential amino acids. As well, I find evidence that physical inactivity alone cannot explain long COVID and ME/CFS symptoms. Where all of long COVID, ME/CFS, and physical inactivity have lower whole-body aerobic capacity, physical inactivity causes a decrease in muscle fibre size, loss of mitochondria, increases in muscle lipotoxic lipids, and decreases in metabolites related to carnitine metabolism. These changes are not seen in either long COVID nor ME/CFS, and support the idea that long COVID and ME/CFS have disease specific muscle changes.

Overall, I find that the reduced whole-body capacity of long COVID and ME/CFS patients is not cause by physical inactivity, and is defined by reduced muscle oxidative ability. The lower amounts of local cells that would normally support exercise and damage responses are lower in both long COVID and ME/CFS, which partially explains the occurrence of PEM. This also suggests that patients experiencing PEM should not undertake normal rehabilitation, however it might be that more individually tailored, and severely monitored approaches may still be beneficial.
Source: Charlton, B. T. (2026). Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology. [PhD-Thesis – Research and graduation internal, Vrije Universiteit Amsterdam]. https://doi.org/10.5463/thesis.1979 https://research.vu.nl/en/publications/explaining-fatigue-and-post-exertional-malaise-in-long-covid-and-/ https://research.vu.nl/ws/portalfiles/portal/517511531/aio01877%20braeden%20charltonfinal%20-%206acf4153820e1.pdf (Full text)

“The Prisoner”

Case Histories of ME/CFS: “The Prisoner”
ProHealth.com
by David S Bell, MD, FAAP
April 4, 2012

This is the case history of a man whose fear of relapse 4 years after sudden onset of ME/CFS nearly robbed him of recovery. It is excerpted from Dr. Bells free e-book Faces of CFS – Case Histories of Chronic Fatigue Syndrome, published in August, 2000 ( David S Bell, MD, 2000).

Reprinted with the kind permission of ProHealth: 4/4/12

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THE PRISONER

It is so ironic that while most doctors see CFS as hypochondriasis, I feel that hypochondriasis may be the result of the combination of CFS and the physician ignorance. Patients must sail these waters without guidance, forcing them to make it on their own.

Those of us in good health rarely appreciate our good fortune. We live our lives ravenously, devouring the minutes of the day with work, play, love – ever eager for the next course. We charge ahead, assuming life will go on as always.

In order to accomplish this, we allow ourselves to be oblivious to the suffering of others. We push their pain to the deep recesses of our subconscious, and remain blind to the fact that around the corner may lie an event that will change the foundation of our lives with similar finality.

Gary Burns was just like the rest of us. There was nothing malevolent about his view of life; he harbored no evil intentions. Yet, he was as unaware of the suffering of others as the rest of the world was about to be of his own suffering.

Like most patients, Gary’s ordeal began with a bout of what he assumed must be flu. He was 37, robust and active, a husband and a father.

This flu announced itself to Gary one day in October of 1986. The course of Gary’s illness, and the eventual dissolution of everything that he had once taken for granted, was typical for an adult who experiences what we doctors call sudden onset of chronic fatigue syndrome (ME/CFS).

Initially, he was offered a months sick leave by his company, a nearby factory. He tried to go back to work when his sick leave ended, but often he felt in a state of collapse by noon, and had to leave the jobsite.

He took an extended leave of absence, hoping for recovery. If he could just catch up on his sleep, he kept telling himself and others, all would be well. Gary had moments during the day when he found the strength to shower, wander through his house, and ponder the possibility of returning to his job. But, soon enough, it would return, and he would tumble onto the sofa and sleep the day away.

Gary still had no idea what it was, and his doctor hadnt a clue, either. Gary had been ill for six months when his doctor announced that he had been unable to discover a medical explanation for Gary’s symptoms.

He advised Gary to snap out of it, to get more exercise, and to see a psychiatrist.

Like a lot of people, Gary trusted his doctor and believed what his doctor had told him. With some embarrassment, and worry over the expense, Gary arranged an appointment with a psychiatrist. After all, he was desperate, and willing to try anything. The psychiatrist probed for information about Gary’s life, and Gary answered the psychiatrists questions honestly.

He said he was in the process of being fired, and that he was going broke.

He confessed he had been unusually irritable, chastising his kids for creating noise and havoc in the house, and sulking whenever his wife tried to comfort him.

In a revelation that was somewhat difficult for him, Gary admitted he was depressed.

The doctor prescribed an antidepressant, and invited Gary to continue therapy in order to resolve emotional conflicts – conflicts that the psychiatrist suggested were the cause of Gary’s disabling illness.

The following day, however, when Gary took the first pill, he rapidly deteriorated, feeling as if he had been hit full force by a freight train.

He slept for two days, and when he was finally able to stay awake, he felt hung over, as if he had drunk a case of liquor the night before. Perhaps not surprisingly, Gary decided to cancel his next appointment.

The psychiatrists secretary insisted the antidepressant could not possibly have caused Gary’s severe reaction. She also advised him he would be charged for the appointment, whether he showed up or not. So much for psychiatry, Gary thought, and never returned. By then, Gary felt as if he was riding a wild and powerful horse, but the reins had slipped from his hands.

Desperation was a daily staple, and as he lay in a helpless mound on his bed, or the sofa, he searched his mind frantically for solutions.

His mother, whom he had frequently accused of being a health nut, owned a health food store. Gary decided to sample the assorted vitamins and nostrums available in his mothers shop. He began eating organic food and taking vitamins for the first time in his life, although he noticed no immediate improvement.

On his worst days, he wondered if he had a terminal illness, especially cancer, that his doctor had missed. He decided to read everything he could about cancer; if the doctors were incapable of discovering the cause of his symptoms, he would become a doctor himself.

In the course of his reading journey, Gary came upon an article that described CFS.

The stories of the patients in this article resonated with his own experience of the disease: sudden onset; a long, chronic course, exhaustion, headaches, pain; sensitivity to light, night sweats, the sensation – if not the reality – of high fever.

He was stunned when he read that patients with CFS are exquisitely sensitive to many drugs, including anti-depressants such as the one he had taken. He felt as if he was reading his own biography. In fact, he was so persuaded that the long-standing mystery of the last year was resolved, he felt incredulous that his doctor had missed the obvious signs, which now seemed so obvious.

There was just one small detail of the disease, as CFS was described in the article, that didnt seem to fit: Gary had never really thought of himself as a Yuppie [with Yuppie Flu].

Certain of his diagnosis, nonetheless, Gary plunged headlong into health nut-ism, with his mothers encouragement and guidance. He eliminated fat from his diet and took handfuls of vitamins. He waded through lengthy discussions of echinacea, germanium, and zinc. Still, he remained unable to work.

Even though previous attempts to exercise had ended in disaster, Gary next decided workouts might be the solution to his nightmare.

He committed himself to pushing past the sore throats and exacerbated fatigue that had followed on the heels of vigorous activity on other occasions. In fact, he gave it everything he had, beginning with a brisk, one-mile walk each day.

On day four, however, when he tried to jog, he felt so suddenly weak at a juncture in the road not far from his house, he wondered whether he would be able to make his way back on two feet. He was completely bedridden for the next two weeks.

Gary felt hopeless.

He had been fired, and most of his friends had dropped him, seeming to have forgotten about everything they had once shared in common.

The medical profession seemed utterly ignorant of his condition.br />

A day rarely passed when he failed to ponder suicide, but the notion of leaving such a traumatic legacy for his children always pulled him up short.

Now, he became exceedingly cautious with his body.

He cloistered himself from the noise and activity of his family.

He woke at nine, downed his vitamins, and showered, and then he rested.

At noon, he ate a health nut lunch of fruits and grains, and then he rested.

In the late afternoons, he attempted a few chores and stretched his muscles in the quiet of his living room. His children stayed with neighbors after school until his wife returned from work.

Together, the family ate a nutritious dinner. Afterward, Gary rested.

At ten, he went to bed, where he lay quietly until he fell asleep at midnight.

Two years of Gary’s life passed in this way.

Most of what was important to him before the onset of CFS had dissolved in those two years. His children became used to their new father, the one who could not play baseball or take them to the county fair. They began to forget their old father.

And then something wonderful happened: Gary started to get better.

The severity of his daily headache lessened, as did the crushing fatigue; he was able to be more active. Gary felt confident that his improvement was due to his adherence to his rigid schedule of the previous two years.

In the third year of his illness he told me he felt he was functioning at about 70% of his pre-CFS activity level.

Still, he planned his days with great care, taking a short walk just twice a week, playing catch with his children each day. He told me proudly that he could ride the lawn mower and cut the entire lawn without stopping to rest in the middle of the job.

It was apparent that he had finally accepted his new life; his despair was gone.

By the fourth year Gary complained only of persistent fatigue, muscle aching, and the fractured, disturbed sleep patterns that are common to virtually all CFS patients, and, in fact, are one of the most pervasive hallmarks of the disease.

Although Gary’s symptoms were less severe than they had been in the past however, he continued his rigid adherence to a reduced level of activity. He believed that his careful attention to what he ate and his meager exercise regime was responsible for his improvement; that he had finally regained control of his destiny.

I became worried – not about the illness, but about Gary’s nearly obsessive concern with over-exerting himself. He had become his own prisoner, caught up in self-imposed rules and regulations that severely limited his experience of the world. One day, I voiced my concerns. I told him that he was both his own jailer and inmate.

I told him he needed to take some risks. I suggested exercise.

His mouth nearly fell open, recalling his own disaster with exercise two years before. Most CFS patients have learned through bitter experience that efforts to surmount their disability and engage in the kind of exercise activities they routinely performed before they fell ill is unlikely to have a good result.

But the problem is not exercise, it is the assumption that exercise will by definition change the course of the illness.

For patients with severe illness, exercise does not change the course and may lead to worsened symptoms.

But if CFS is getting better, exercise is great and may speed the recovery.

I suspected Gary was no longer in the severe illness category. In fact, I was uncertain whether his reduced activity level, which continued to hover around 70% of what was normal for him, was due to CFS, or due to physical de-conditioning as a result of his fear of exertion.

After all, he had been monitoring himself like an organism under a microscope for three years. Granted, he had learned the brutal limits of his disease through suffering, but it seemed to me that he was becoming almost hypochondriacal in his attention to his body.

It is so ironic that while most doctors see CFS as hypochondriasis, I feel that hypochondriasis may be the result of the combination of CFS and the physician ignorance. Patients must sail these waters without guidance, forcing them to make it on their own.

Of course, the only way to find out was to ask Gary to exercise, and he and I both knew the proposition was risky.

Which is better: to exist safely in a compulsively rigid way of life? Or try for a full-out, 100% return to normalcy – at the risk of initiating a relapse that might turn the clock back for Gary by months or even years?

Gary reminded me that it was his life I was risking by making such a request, not my own. Good point. I was asking him to throw away his fear of the pain and suffering of the past years, all the while courting its return. Did I have that right? I had come to know Gary well by then. My observations and intuition led me to believe that Gary was going to be one of the lucky ones; he was going to beat the illness.

All signs pointed to continued improvement.

If my suspicions were in error, I thought, Gary would have a relapse, but he would likely recover from it within a month.

And, more importantly, at least we would have our answer. He would still be a prisoner, but he would be prisoner of the disease, not his own fear.

After a great deal of discussion, Gary finally agreed to try.

We planned an exercise program that was extremely gentle.

Most healthy people wouldnt have considered it an exercise program at all.

We planned stretching exercises, then slow walking, then brisk walking – depending upon the progress, if any.

When Gary joked that he was dedicating his body to science, his wife frowned. In the beginning, Gary experienced significant anxiety, and increased muscle aching, as well. But, over a period of weeks, the quality of his sleep began to improve, along with a decrease in the muscle pain.

In fact, at the end of two months, it was clear to Gary and to me that he was better.

And when his fear began to diminish, he became more willing to venture out into the world of the living. After three months, he had even more energy, and felt confident and enthusiastic about life to a degree he had not experienced for years.

This is not to say his fatigue evaporated. He was tired, sometimes very tired. But, as Gary pointed out, it was good tiredness, not a CFS tiredness.

In the complicated realm of CFS, where there remain so many unanswered questions, I am not sure what recovery actually means.

I often wonder whether the illness vanishes completely, leaving the patient the same as before,

Or if it simply recedes in the background, becoming mild enough that the patient learns to ignore its nagging distractions.

Both probably occur.

In a study Mary Robinson did of our patients, 20% remained disabled after 15 years. Of the remaining 80%, half persisted with symptoms although they were able to lead relatively normal lives.

Several years have passed for Gary and we continue to stay in touch. He has clearly entered that privileged circle of CFS patients who actually recover fully from the disease. I do not think that his continued recovery can be attributed to exercise, or even the vitamins, but who knows?

I do feel that if Gary had not tried the exercise, he would have stayed in his prison for the rest of his life. Gary recovered for reasons that are mysterious, but he needed to take a leap of faith in order to demonstrate the recovery to himself.

Gary doesnt really think about these issues very much anymore. He is working again, and engaged once more in the lives of his spouse and children. Nevertheless, he has been changed profoundly by his experience. He left his prison of four years, but as a different man. He carries with him an appreciation of his incredible good luck. His suffering now is confined to feeling the suffering of others who are in pain.

When he watches the news on television, and there is a story about AIDS or multiple sclerosis or cancer or CFS, he does not rush to change the channel as he once might have done.

Instead, his eyes fill with tears.

– David S Bell, MD, Aug 15, 2000

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Note: This information represents the experience and opinions of Dr. David Bell. It is generic and for general information purposes only. ME/CFS/FM is an extremely complex illness, and such general information may not be appropriate for an individual with this illness. Therefore, should you be interested in the ideas presented here, please discuss them with your personal physician.

Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome

Abstract:

Background: Two consecutive cardiopulmonary exercise tests (CPETs) performed 24 hours apart are increasingly used to determine post-exertional malaise (PEM) and disability in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Declines in functional capacity on Day 2 reflect impaired recovery and PEM. However, reports have variably described a reduction in peak oxygen consumption (VO2) and/or VO2 at the anaerobic ventilatory threshold (VT). Given the inconsistent findings, we sought to replicate the studies by performing sequential 2-day CPETs in ME/CFS and age- and sex-matched sedentary controls.

Methods: Accordingly, maximal bicycle ergometer CPETs were performed on two consecutive days in 58 patients with ME/CFS (mean age 38.6 ± 9.6 years, Body Mass Index (BMI) 24.1 ± 3.3 kg/m2, 11 men and 47 women) and 25 age-matched sedentary control (CON) subjects (age 38.2 ± 9.9 years, BMI 24.2 ± 3.4 kg/m2, 5 men and 20 women). Peak VO2 was reported as the highest 30-sec average; VT was selected as the nadir of the VE/VO2 and PETCO2 curves, and VE/VCO2 as the slope throughout exercise.

Findings: For ME/CFS and CON subjects, there were no significant changes in Peak VO2 between Day 1 and Day 2 studies (ME/CFS Day 1, 22.3 ± 5.4; Day 2, 22.5 ± 5.4 mL·kg-1·min-1; CON Day 1, 23.4 ± 3.5; Day 2, 22.8 ± 3.6 mL·kg-1·min-1; NS). Similarly, VO2VT and VE/VCO2 slopes were not significantly different between the ME/CFS patients and CON, and on Day 2, they did not show any differences within or between groups. Peak heart rate was significantly higher in CON versus ME/CFS. The level of perceived exertion was significantly greater at all levels of exercise on the Day 1 and Day 2 tests for ME/CFS patients versus CON.

Interpretation: Our data indicate that 2-day CPET provides exercise-related results that are the same in ME/CFS patients and CON subjects. ME/CFS patients have a greater perception of exertion throughout exercise and a lower maximum heart rate than CON. The data do not support using the 2-day CPET protocol to define PEM or disability.

Source: Mancini DM, Cook DB, Brunjes DL, Soto T, Blate M, Quan P, Yamazaki T, Norweg A, Natelson BH. Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome. Front Physiol. 2026 May 13;17:1816082. doi: 10.3389/fphys.2026.1816082. PMID: 42212259; PMCID: PMC13213420. https://pmc.ncbi.nlm.nih.gov/articles/PMC13213420/ (Full text)

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)

ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid are characterized by post-exertional malaise (PEM). Similarities in disease presentation suggest important commonalities in bioenergetic impairment, but this hypothesis has not been demonstrated. The metabolic underpinnings of each disease can be elucidated by two cardiopulmonary exercise tests (CPET) administered 24 hours apart. This retrospective study examined physiological responses on two-day CPET in people with ME/CFS (63 females and 21 males), Long Covid (52 females and 27 males), and matched non-disabled control participants (51 females and 20 males).

Data were analyzed within sexes using repeated measures analysis of variance. All participants met maximal effort criteria. There were significant reductions in oxygen consumption (O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion. Performance decrements were observed in both sexes.

Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long Covid both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes.

Findings support the utility of two-day CPET as an objective measure of PEM and functional impairment. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.

Source: Todd Davenport, Staci Stevens, Jared Stevens et al. ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing, 22 January 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8606329/v1] https://www.researchsquare.com/article/rs-8606329/v1 (Full text available as PDF file)

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)