Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence
ABSTRACT Background Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessiv...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.13669 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850222116466589696 |
|---|---|
| author | Carmen Scheibenbogen Klaus J. Wirth |
| author_facet | Carmen Scheibenbogen Klaus J. Wirth |
| author_sort | Carmen Scheibenbogen |
| collection | DOAJ |
| description | ABSTRACT Background Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept. Methods We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC‐ME/CFS). Results Mitochondrial dysfunction is a long‐held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC‐ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton‐sodium exchange due to anaerobic metabolism and diminished activity of the sodium‐potassium‐ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise‐induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion. Conclusion Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters. |
| format | Article |
| id | doaj-art-ab368fc4cb754f1183316de499d40354 |
| institution | OA Journals |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-ab368fc4cb754f1183316de499d403542025-08-20T02:06:27ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-02-01161n/an/a10.1002/jcsm.13669Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated EvidenceCarmen Scheibenbogen0Klaus J. Wirth1Institute of Medical Immunology Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin and Berlin Institute of Health (BIH) Berlin GermanyMitodicure GmbH Kriftel GermanyABSTRACT Background Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept. Methods We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC‐ME/CFS). Results Mitochondrial dysfunction is a long‐held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC‐ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton‐sodium exchange due to anaerobic metabolism and diminished activity of the sodium‐potassium‐ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise‐induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion. Conclusion Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.https://doi.org/10.1002/jcsm.13669long COVIDmitochondrial damagemyalgic encephalomyelitis/chronic fatigue syndromepost–COVID‐19skeletal musclevascular dysfunction |
| spellingShingle | Carmen Scheibenbogen Klaus J. Wirth Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence Journal of Cachexia, Sarcopenia and Muscle long COVID mitochondrial damage myalgic encephalomyelitis/chronic fatigue syndrome post–COVID‐19 skeletal muscle vascular dysfunction |
| title | Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence |
| title_full | Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence |
| title_fullStr | Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence |
| title_full_unstemmed | Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence |
| title_short | Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence |
| title_sort | key pathophysiological role of skeletal muscle disturbance in post covid and myalgic encephalomyelitis chronic fatigue syndrome me cfs accumulated evidence |
| topic | long COVID mitochondrial damage myalgic encephalomyelitis/chronic fatigue syndrome post–COVID‐19 skeletal muscle vascular dysfunction |
| url | https://doi.org/10.1002/jcsm.13669 |
| work_keys_str_mv | AT carmenscheibenbogen keypathophysiologicalroleofskeletalmuscledisturbanceinpostcovidandmyalgicencephalomyelitischronicfatiguesyndromemecfsaccumulatedevidence AT klausjwirth keypathophysiologicalroleofskeletalmuscledisturbanceinpostcovidandmyalgicencephalomyelitischronicfatiguesyndromemecfsaccumulatedevidence |