E3 PreliminaryPreliminaryPEM not requiredMechanisticPeer-reviewedReviewed
Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation.
Jothi, Swathi, Insel, Michael, Claessen, Guido et al. · Physiological reports · 2025 · DOI
Quick Summary
This study compared how bodies use oxygen during exercise in people with long COVID, ME/CFS, and healthy controls. Researchers found that both long COVID and ME/CFS patients had trouble getting oxygen into their muscles during exercise, which was the main reason they couldn't exercise as much as healthy people. If this muscle oxygen problem could be fixed, it might significantly improve exercise ability in both conditions.
Why It Matters
This study identifies a shared physiologic mechanism between long COVID and ME/CFS that could explain exercise intolerance in both populations. By pinpointing skeletal muscle oxygen diffusion as a key problem, it opens potential therapeutic targets for improving exercise capacity. Understanding this mechanism is crucial for developing evidence-based treatments rather than relying on symptom management alone.
Observed Findings
- Both PASC and CFS/ME patients had significantly reduced peak oxygen consumption compared to healthy controls.
- Skeletal muscle oxygen diffusion capacity (DM) was the most impaired oxygen transport parameter in both patient groups (p = 0.01).
- Mathematical correction of DM alone predicted V̇O₂peak improvement of 66% in PASC patients (p = 0.008) and 34.7% in CFS/ME patients (p = 0.06).
- Other oxygen transport parameters (lung diffusion, cardiac output, hemoglobin) did not show comparable impairment in both conditions.
Inferred Conclusions
- Impaired skeletal muscle oxygen diffusion is a shared pathophysiologic mechanism of exercise intolerance in both long COVID and ME/CFS.
- Peripheral oxygen extraction defect represents a dominant limiting factor in exercise capacity for both conditions.
- Skeletal muscle oxygen diffusion may represent a viable therapeutic target for improving exercise tolerance in these conditions.
Remaining Questions
- What causes the skeletal muscle oxygen diffusion defect in these conditions—is it mitochondrial dysfunction, capillary density reduction, or other mechanisms?
- Would interventions targeting skeletal muscle oxygen diffusion actually improve symptoms and exercise capacity in real patients?
What This Study Does Not Prove
This study does not prove that fixing skeletal muscle oxygen diffusion will actually improve symptoms in patients—only that the mathematical model suggests potential benefit. The small sample size means findings may not apply to all ME/CFS or long COVID patients. The study identifies correlation between impaired oxygen diffusion and exercise limitation but cannot definitively establish causation or rule out other contributing mechanisms.
Tags
Symptom:Post-Exertional MalaiseFatigue
Biomarker:MetabolomicsBlood Biomarker
Phenotype:Infection-TriggeredLong COVID Overlap
Method Flag:Small SampleExploratory OnlyWeak Case DefinitionPEM Not Defined
Metadata
- DOI
- 10.14814/phy2.70535
- PMID
- 40892700
- Review status
- Editor reviewed
- Evidence level
- Early hypothesis, preprint, editorial, or weak support
- Last updated
- 12 April 2026
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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