Exercise Physiology and Muscle Biology
1 Largest Two-Day CPET Study
Principal Investigator:: Multiple groups
Institution:: Multi-centre (USA)
Contact/URL:: https://doi.org/10.1186/s12967-024-05410-5
Funder:: Institutional
Status:: Published 2024
Phase:: Observational (physiological testing)
Cohort:: Largest 2-day CPET cohort in ME/CFS to date
Mechanism/Focus:: Two-day cardiopulmonary exercise testing to objectively measure post-exertional malaise. Significant reductions in VO2 and workload at the ventilatory anaerobic threshold (VAT) on day 2 in ME/CFS versus controls. Implicates autonomic dysregulation of blood flow and oxygen delivery for energy metabolism.
Primary Outcomes:: Impaired recovery after exertional stressor; cardiac, pulmonary, and metabolic contributions to exertion intolerance; larger effect sizes at VAT than peak
Estimated Completion:: Published
Publication Medium:: Journal of Translational Medicine
Document Relevance:: Ch. 6 (energy metabolism), Ch. 10 (cardiovascular), Ch. 20 (biomarker research—2-day CPET as objective PEM marker)
The 2-day CPET protocol remains the gold standard for objectively demonstrating PEM. This largest study to date substantiates that the day-2 decrement is reproducible across diverse ME/CFS cohorts (Keller et al. 2024). The finding that cardiac, pulmonary, and metabolic factors all contribute to exertion intolerance supports the multi-system model in Ch. 13 rather than any single-organ explanation.
2 Skeletal Muscle Properties in Long COVID and ME/CFS
Principal Investigator:: Multiple groups
Institution:: Multi-centre (Netherlands / Europe)
Contact/URL:: https://doi.org/10.1101/2025.05.02.25326885
Funder:: Institutional
Status:: Preprint May 2025
Phase:: Observational (muscle biopsy)
Cohort:: Long COVID and ME/CFS patients versus controls
Mechanism/Focus:: Muscle biopsies analysed for mitochondrial markers, WASF3 protein, ER stress markers. Found elevated WASF3 and ER stress with decreased mitochondrial Complex IV subunits. Critically, muscle abnormalities differed from those seen in bed rest deconditioning.
Primary Outcomes:: ME/CFS muscle pathology is distinct from deconditioning; WASF3 elevation confirmed in skeletal muscle tissue
Estimated Completion:: Preprint published; peer review pending
Publication Medium:: medRxiv
Document Relevance:: Ch. 6 (energy metabolism—WASF3), Ch. 17 (lifestyle interventions—exercise contraindications)
This study provides crucial evidence against the deconditioning hypothesis: if ME/CFS fatigue were due to simple disuse, muscle changes should resemble bed rest patterns (2025). The distinct pathology (WASF3 elevation, mitochondrial complex loss) aligns with the NIH WASF3 findings (Wang et al. 2023) and supports a disease-specific metabolic myopathy rather than secondary deconditioning.