Tag: PEM

Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID-19 syndrome share a symptom profile, including severe fatigue, cognitive dysfunction, exertional intolerance, sleep disturbances, hypervigilance, and the paradoxical state of being “wired but tired.” A well-established finding is sympathetic hyperactivity with reduced vagal tone, typically interpreted as autonomic nervous system dysfunction. Emerging evidence, however, suggests a broader disturbance across multiple neurotransmitter systems.

This paper reviews current knowledge on neurotransmitter systems implicated in ME/CFS and Long COVID, focusing on potential mechanisms of dysregulation and their roles in disease pathology and symptom generation, as well as implications for treatment. In addition to abnormalities of the noradrenergic system, disturbances in serotonergic, GABAergic, and glutamatergic signaling have been reported. Contributing factors may include autoimmunity, neuroinflammation, gut dysbiosis, epigenetic influences, and stressors such as orthostatic intolerance, metabolic strain, and pain.

A shift favoring excitatory over inhibitory neurotransmission can lead to excessive neural activation, autonomic dysfunction, sensory hypersensitivities, sleep disturbances, and cognitive impairment. Reduced GABAergic tone combined with increased glutamatergic and noradrenergic activity may elevate skeletal muscle tone, contributing to calcium overload, mitochondrial dysfunction, exertional intolerance, and post-exertional malaise. Various pharmacological treatments may partially rebalance these neurotransmitter systems, but limited efficacy highlights the need for systematic investigation and individualized strategies.

Source: Wirth KJ, Scheibenbogen C. Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2026 Apr 30;27(9):4041. doi: 10.3390/ijms27094041. PMID: 42123618. https://www.mdpi.com/1422-0067/27/9/4041 (Full text)

Interpreting hand grip strength in hospital employees with post-COVID syndrome compared to non-infected controls: a case-control study

Abstract:

Post-COVID syndrome (PCS) is characterized by a variety of persistent symptoms following SARS-CoV-2 infection, including fatigue among others. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a related neurological disorder primarily characterized by severe fatigue and post-exertional malaise. This exploratory study aimed to assess hand grip strength (HGS) in individuals with PCS to evaluate muscular performance and fatigability and to explore potential HGS-derived parameters associated with PCS.

HGS was measured in 19 hospital employees with PCS (mean age 47.8; 89.5% female; 7 fulfilling ME/CFS criteria) and compared with 23 healthy controls (mean age 43.7; 69.6% female). Measurements were performed in two sessions separated by 60 min, each consisting of ten consecutive HGS measurements. Linear mixed model analysis indicated that HGS tended to be lower in PCS at specific measurement points, although no consistent overall group effect was observed. HGS was reduced in the second session in PCS but not in controls, suggesting possible alterations in recovery following repeated exertion.

Exploratory analysis of 30 HGS-derived parameters using logisitic regression models in female participants identified parameters based on maximum, minimum, and mean force values as showing the most promising discriminatory patterns: however, predictive performace was moderate and should be interpreted with caution.

Overall, HGS may provide insights into funcitional impairment in PCS and could serve as a supportive adjunct in clinical assessment, although its diagnostic utility requires validation in larger cohorts.

Source: Tack M, Gruber R, Betting L, Herbrandt S, Schlang G, Mattner F. Interpreting hand grip strength in hospital employees with post-COVID syndrome compared to non-infected controls: a case-control study. Sci Rep. 2026 May 9. doi: 10.1038/s41598-026-51666-w. Epub ahead of print. PMID: 42103832. https://www.nature.com/articles/s41598-026-51666-w (Full study available as PDF file)

Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases

Abstract:

Background: Post-exertional malaise (PEM), which is the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is also reported in a proportion of patients with post-COVID-19 syndrome (PCS). Our objective was to identify determinants that may be linked to the emergence of PEM in PCS patients.

Methods: Patients fulfilling the World Health Organization definition for PCS who attended the post-COVID unit of the Internal Medicine Department of Angers University Hospital, France, between June 2020 and December 2023 were included retrospectively. Their medical records were reviewed to extract information on COVID-19 infection history, characteristics of post-exertional malaise (PEM), fatigue severity, and relevant epidemiological variables.

Results: The study included 220 patients, grouped according to whether post-exertional malaise was present (PCS/PEM+) or absent (PCS/PEM-). PEM was observed in 26.4% of patients and was significantly linked to earlier COVID onset in 2020/2021 (OR 5.68 (95% CI: 1.66-19.45), p = 0.006), as well as higher fatigue levels (OR 2.07 (95% CI: 1.22-3.50), p = 0.007).

Conclusions: Patients who contracted COVID-19 during the pre-Omicron period reported PEM more frequently than those infected in later waves. This observation could reflect differences in viral characteristics following the emergence of the Omicron variant; however, alternative explanations-such as increasing vaccination coverage, accumulating post-infectious immunity, or other unmeasured factors-cannot be ruled out. Based on the observed link between PEM and symptom severity, PCS patients should be systematically assessed for the presence of PEM.

Source: Ghali A, Lavigne C, Ghali M, Lacombe V. Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases. J Clin Med. 2026 Apr 13;15(8):2948. doi: 10.3390/jcm15082948. PMID: 42074751. https://www.mdpi.com/2077-0383/15/8/2948 (Full text)

A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID

Abstract:

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a neuroimmune disease characterized by debilitating post-exertional malaise (PEM), brain-fog/cognitive problems, and dysregulation of the autonomic nervous system. Currently, there are no objective biomarkers for ME/CFS despite decades of research.

Here, we compile evidence from literature that supports taste dysfunction, particularly alterations of taste perception mediated by Type II taste receptor cells, may be a critical underrecognized feature of ME/CFS. The impetus is drawn from the emerging evidence of clinicopathological similarities between long-COVID and ME/CFS. We discuss in parallel the mechanisms of cellular metabolism, inflammation, vascular dysfunction, and autonomic dysregulation in ME/CFS and long-COVID pathophysiology.

We postulate that mechanistically, dysregulation of ATP signaling through P2X2/P2X3 purinergic receptors underlies both gustatory impairment and core ME/CFS symptoms. Adopting information from the NIH-RECOVER shared resources, we present evidence that suggests chemosensory dysfunction as a potential indicator of progression/severity of PEM. We discuss standardized taste testing as a non-invasive screening tool complementary to molecular biomarkers for ME/CFS.

Notwithstanding, we acknowledge the limitations, confounding and contributing factors such as medications and deficiencies that may exacerbate or independently cause taste-related symptoms in ME/CFS.

In conclusion, we present a compelling case for the multi-factorial role of taste dysfunction in ME/CFS and suggest specific research priorities for investigating the relationship between chemosensory function and post-viral chronic illness.

Source: Srinivasan M, Joseph PV. A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID. Front Med (Lausanne). 2026 Apr 8;13:1808646. doi: 10.3389/fmed.2026.1808646. PMID: 42040552; PMCID: PMC13107777. https://pmc.ncbi.nlm.nih.gov/articles/PMC13107777/ (Full text)

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

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)

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)