Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence.
Scheibenbogen, Carmen, Wirth, Klaus J · Journal of cachexia, sarcopenia and muscle · 2025 · DOI
Quick Summary
This review brings together recent research showing that ME/CFS involves problems in the muscles themselves, particularly damage to mitochondria (the energy-producing structures inside cells) and an imbalance of salt and calcium in muscle tissue. When muscles don't get enough oxygen, they switch to a less efficient way of making energy, which causes sodium (salt) to build up inside cells, triggering calcium overload that damages mitochondria. This cascade of damage may explain why patients experience severe fatigue and feel much worse after exercise.
Why It Matters
This synthesis of recent muscle pathology research provides the strongest evidence to date for a specific biological mechanism underlying ME/CFS symptoms, moving beyond speculation toward targetable dysfunction. Understanding that the problem resides in muscle tissue rather than systemic immune dysfunction opens new treatment avenues and validates the reality of the disease for patients and clinicians. This work also helps explain why only some post-COVID patients progress to ME/CFS, identifying specific risk factors and mechanisms.
Observed Findings
- Electron microscopy showed mitochondrial damage in skeletal muscle of ME/CFS patients with preferential subsarcolemmal localization, but not in post-COVID patients without ME/CFS.
- MRI studies demonstrated elevated intracellular sodium levels in ME/CFS patient muscles that inversely correlated with hand grip strength.
- Muscle biopsies taken one day after exercise in PC-ME/CFS patients showed simultaneous presence of muscle necrosis and regenerative changes.
- Diminished hand grip strength correlated with symptom severity and prognosis in ME/CFS patients.
- Histological investigations excluded ischemia from microvascular obstruction, active viral infection, and immune myositis as causes of muscle damage.
Inferred Conclusions
- Sodium and calcium ionic imbalance triggered by anaerobic metabolism during tissue hypoperfusion is the primary mechanism of mitochondrial damage and muscle injury in ME/CFS.
- Repeat cycles of exercise-induced muscle damage and incomplete recovery create a vicious cycle of energy deficit that explains post-exertional malaise and exertional intolerance.
- Mitochondrial dysfunction in skeletal muscle (but not leukocytes) is the key pathophysiological feature distinguishing ME/CFS from other conditions.
- Certain post-COVID patients develop ME/CFS specifically because of muscle tissue vulnerability to hypoperfusion-induced ionic dysregulation.
Remaining Questions
- What causes the initial muscle hypoperfusion in ME/CFS, and why does it persist despite no evidence of microvascular obstruction?
- Why do some post-COVID patients develop muscle pathology and ME/CFS while others recover completely?
- Would treatments targeting sodium-potassium-ATPase dysfunction or restoring perfusion actually reverse muscle pathology and improve symptoms?
- Are the muscle pathology changes sufficient to explain all cardinal ME/CFS symptoms, or are there additional pathophysiological mechanisms in the nervous or immune systems?
What This Study Does Not Prove
This review does not prove causation—elevated sodium and mitochondrial damage are correlated with disease but the temporal sequence and whether they are primary or secondary to other processes remains incompletely established. The review also does not establish why hypoperfusion occurs in ME/CFS muscle tissue, only that its consequences fit observed pathology. Additionally, findings from small biopsy studies in selected patients may not represent all ME/CFS patients or all muscle groups.
Topics
Tags
Metadata
- DOI
- 10.1002/jcsm.13669
- PMID
- 39727052
- Review status
- Editor reviewed
- Evidence level
- Established evidence from major reviews, guidelines, or evidence maps
- Last updated
- 7 April 2026