Fanò-Illic et al. (2026)
- Authors: Giorgio Fanò-Illic, Francesco Coscia, Paola V. Gigliotti, Franco Checcaglini, Ugo Carraro, Stefania Fulle, Rosa Mancinelli
- Institutes: Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy, IIM—Interuniversity Institute of Myology, Italy
- Publisher: Diagnostics (MDPI)
- Link: DOI
Summary
This comprehensive review establishes ME/CFS as a biological, muscle-centric metabolic disorder, providing a strong rationale for diagnostic testing focused on mitochondrial health. By identifying specific failures in muscle energy production and calcium regulation, it shifts the focus from symptom management to the investigation of primary physiological defects. The integration of molecular evidence helps validate patient experiences of exercise intolerance as a direct consequence of cellular dysfunction.
What was researched?
This review examines the physiological and molecular mechanisms of skeletal muscle involvement in ME/CFS, specifically looking at oxidative stress, mitochondrial function, and energy regulation.
Why was it researched?
The study was conducted to move beyond psychological interpretations of ME/CFS by synthesizing decades of research into a biological framework that explains muscle fatigue and post-exertional malaise.
How was it researched?
The authors performed a narrative synthesis of scientific literature published between 1990 and 2025, integrating clinical, biochemical, and experimental data from patient muscle biopsies and cellular models.
What has been found?
The research identifies ME/CFS as a muscle-metabolic disorder characterized by mitochondrial oxidative distress, redox imbalance, and impaired calcium handling within muscle cells. These abnormalities are primary defects rather than secondary effects of deconditioning and directly contribute to impaired energy production and the clinical hallmark of post-exertional malaise.
Discussion
The authors discuss how these muscle-specific alterations overlap with symptoms seen in Long COVID and aging. They highlight the potential for using the muscle secretome and specific redox markers as objective, non-invasive diagnostic biomarkers in the future.
Conclusion & Future Work
Skeletal muscle is a central player in ME/CFS pathophysiology, requiring a shift toward metabolic and neuromuscular diagnostic approaches. Future translational research should prioritize developing therapies that target mitochondrial health and restore calcium homeostasis in muscle tissue.