Tag: PEM

Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multisystemic disorder characterized by severe, persistent fatigue not alleviated by rest and worsened by minimal exertion, often accompanied by post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and autonomic disturbances. Despite decades of research, its pathophysiology remains incompletely understood, and skeletal muscle involvement has only recently gained attention.

This review aims to provide a historical and pathophysiological synthesis of ME/CFS, emphasizing the pivotal role of skeletal muscle in the onset and persistence of symptoms, and to integrate molecular, cellular, and pathophysiological evidence into a coherent explanatory framework.

This is a narrative review of published literature (1990-2025) with critical integration of clinical, biochemical, and experimental data on oxidative stress, mitochondrial dysfunction, Excitation-Contraction (E-C coupling) dysregulation, and muscle secretome alterations in ME/CFS also in relation to post-viral syndromes (e.g., Long COVID).

Evidence consistently points to mitochondrial oxidative stress, redox imbalance, impaired Ca2+ handling, and altered signaling pathways in skeletal muscle of patients with ME/CFS. Historical milestones show an evolution from psychogenic interpretations toward recognition of ME/CFS as a biological disorder with neuromuscular and metabolic underpinnings.

ME/CFS can be interpreted as a skeletal muscle-metabolic disorder characterized by oxidative distress, mitochondrial dysfunction, and impaired energy regulation, leading to the clinical picture of exercise intolerance and post-exertional malaise. Integrating basic and clinical research through a translational approach provides the foundation for new diagnostic tools, targeted therapies, and biomarkers.

Source: Fanò-Illic G, Coscia F, Gigliotti PV, Checcaglini F, Carraro U, Fulle S, Mancinelli R. Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement. Diagnostics (Basel). 2026 Mar 28;16(7):1019. doi: 10.3390/diagnostics16071019. PMID: 41975732. https://www.mdpi.com/2075-4418/16/7/1019 (Full text)

Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle

Abstract:

Objective: M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear.

Results: Our study showed that hemizygous deletion of the early autophagy gene atg13 (Tg+/-ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, and increases reactive oxygen species (ROS) levels in splenic macrophages, leading to M1 polarization. After reducing the expression of the autophagy markers WDFY3 and LC3, flow cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), decreasing oxygen metabolism, as evaluated by the ROS-sensor dye DCFDA, and Seahorse oxygen consumption studies revealed that ablation of the atg13 gene impairs mitochondrial function, triggering M1 polarization.

Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages and contributing to the inflammatory response in M1Mφs. Additionally, ablation of the atg13 gene resulted in increased infiltration of M1Mφs into the muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise.

Conclusions: Our study shows that impaired ATG13-driven autophagy increases inflammation through sirtuin-1 inactivation and NF-κB activation, suggesting a role for ATG13 in post-exertional malaise (PEM).

Source: Toriola MA, Timlin E, Bulbule S, Reyes A, Adedeji OM, Gottschalk CG, Barua A, Arnold LA, Roy A. Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle. Inflamm Res. 2026 Jan 27;75(1):26. doi: 10.1007/s00011-025-02158-6. PMID: 41591477; PMCID: PMC12847126. https://pmc.ncbi.nlm.nih.gov/articles/PMC12847126/ (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

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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)

Identifying post-exertional malaise subtypes: Differentiating physical and mental PEM manifestations

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic illness with post-exertional malaise (PEM) as a key symptom. This study categorized participants with ME/CFS who met PEM criteria into four groups based on severity of physical and mental PEM: severe physical PEM (Physical group), severe mental PEM (Mental group), both severe (Both group), or neither severe (Neither group). A control group was also included.

The Both group exhibited the highest symptom severity, while the Neither group displayed lower scores. The Neither group experienced less disability than other ME/CFS subtypes but was significantly more disabled than Controls. Health assessments revealed that Controls had the highest functioning, followed by the Neither group, with the Both group showing greatest impairment. These results indicate distinct PEM subtypes, emphasizing the need to recognize different manifestations of this complex symptom. Future research should include diverse control groups, longitudinal data, and biological measures to further understand PEM subtypes.

Source: Tuzzolino K, Jason LA, Furst J. Identifying post-exertional malaise subtypes: Differentiating physical and mental PEM manifestations. J Health Psychol. 2026 Feb 28:13591053261420598. doi: 10.1177/13591053261420598. Epub ahead of print. PMID: 41761780. https://pubmed.ncbi.nlm.nih.gov/41761780/

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)

Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.

The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.

Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Source: Nunes M, Kell L, Slaghekke A, Wüst RC, Fielding BC, Kell DB, Pretorius E. Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system. Cell Death Dis. 2026 Jan 9;17(1):16. doi: 10.1038/s41419-025-08162-2. PMID: 41513611; PMCID: PMC12789617. https://pmc.ncbi.nlm.nih.gov/articles/PMC12789617/ (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/