The Role of Skeletal Muscle Pathophysiology in ME/CFS and Post-COVID Syndrome

By SWA

The latest research:  "Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence"

A growing body of research highlights skeletal muscle pathophysiology—specifically mitochondrial dysfunction and ionic imbalances—as a key driver of these symptoms. Emerging evidence also suggests that a subset of individuals suffering from post-COVID syndrome (PCS) may develop ME/CFS-like symptoms, referred to as PC-ME/CFS, due to shared underlying mechanisms. This article collects, summarizes, and discusses the current state of knowledge on skeletal muscle dysfunction in ME/CFS and the risk factors contributing to the development of PC-ME/CFS.

Skeletal Muscle Pathophysiology in ME/CFS

In ME/CFS, skeletal muscle dysfunction is thought to play a central role in symptoms like exercise intolerance, persistent fatigue, and PEM. Unlike the temporary fatigue healthy individuals experience, these symptoms are disproportionately severe and worsen after exertion. Research reveals several critical abnormalities in skeletal muscle in ME/CFS patients:

1. Mitochondrial Damage in Muscle Cells

Mitochondria are the "powerhouses" of cells, producing the energy molecule ATP needed for muscle contraction and other cellular functions. In ME/CFS, studies using electron microscopy have shown structural damage to mitochondria in skeletal muscle. This damage is particularly concentrated near the sarcolemma (the outer membrane of muscle cells). Interestingly, these abnormalities are absent in individuals with PCS who do not exhibit ME/CFS-like symptoms, suggesting distinct mechanisms in PC-ME/CFS.

2. Muscle Damage and Repair

Muscle biopsies taken after physical activity in ME/CFS patients reveal signs of necrosis (muscle cell death) alongside evidence of regeneration. This simultaneous damage and repair cycle suggests repeated injury to muscle tissue, likely due to metabolic stress during exertion. This ongoing process aligns with the hallmark symptom of PEM, where physical activity exacerbates symptoms and requires an extended recovery period.

3. Ionic Imbalances and Weakness

Hand grip strength (HGS), a marker of overall muscle strength, is consistently lower in ME/CFS patients and correlates with disease severity. MRI studies have identified elevated intracellular sodium levels in the skeletal muscle of ME/CFS patients, which inversely correlates with HGS. These findings suggest that sodium accumulation disrupts normal muscle function.

PC-ME/CFS: Why Do Some PCS Patients Develop ME/CFS-Like Symptoms?

While many individuals recover from post-COVID syndrome (PCS), a subset develops symptoms resembling ME/CFS. This condition, referred to as PC-ME/CFS, may share the same underlying mechanisms as ME/CFS. Several factors may predispose PCS patients to develop PC-ME/CFS:

1. Persistent Metabolic Dysfunction

SARS-CoV-2 infection can leave long-lasting metabolic disturbances, including mitochondrial dysfunction and ionic imbalances in skeletal muscle. In some PCS patients, these disruptions may persist, leading to symptoms consistent with ME/CFS.

2. Chronic Inflammation and Oxidative Stress

A prolonged inflammatory response or oxidative stress following COVID-19 may impair mitochondrial function, contributing to muscle dysfunction. This mechanism parallels what is observed in ME/CFS.

3. Pre-Existing Vulnerabilities

Individuals with genetic predispositions, a history of viral infections, or conditions such as dysautonomia may have an increased risk of developing PC-ME/CFS after a COVID-19 infection.

4. Post-Viral Autoimmune Response

In some cases, SARS-CoV-2 infection may trigger an autoimmune response targeting ion channels or muscle components, leading to persistent ionic imbalances and muscle dysfunction.

Mechanisms Driving Skeletal Muscle Dysfunction

The dysfunction observed in skeletal muscle appears to be driven by disruptions in ionic balance and mitochondrial energy production, creating a self-perpetuating "vicious cycle":

1. Ionic Imbalances

Ionic balance is crucial for muscle function, including contraction, relaxation, and energy production. This balance relies on the proper concentrations of sodium (Na⁺), potassium (K⁺), and calcium (Ca²⁺) ions inside and outside muscle cells.

  • Sodium Overload: In ME/CFS, increased reliance on anaerobic metabolism during physical activity leads to excessive proton-sodium exchange, resulting in sodium buildup inside muscle cells.
  • Calcium Overload: Sodium overload disrupts sodium-calcium exchange, causing calcium to accumulate in the cell. Calcium overload damages mitochondria, triggers oxidative stress, and impairs energy production.

2. Mitochondrial Dysfunction

Excess calcium and oxidative stress damage mitochondria, reducing their ability to produce ATP efficiently. This energy deficit explains the profound fatigue and muscle weakness in ME/CFS patients. Additionally, mitochondrial dysfunction prevents the muscle from meeting energy demands during physical activity, leading to PEM.

3. Sodium-Potassium Pump Dysfunction

The sodium-potassium pump, which uses ATP to maintain ionic gradients by transporting sodium out of cells and potassium into cells, is less active in ME/CFS patients. This impaired pump function exacerbates ionic imbalances, further reducing energy production and worsening muscle fatigue.

Future Treatment Approaches

Understanding the role of skeletal muscle pathophysiology in ME/CFS and PC-ME/CFS provides new opportunities for targeted treatment strategies. Current and potential approaches include:

1. Restoring Ionic Balance

Therapies aimed at normalizing ionic concentrations within muscle cells could alleviate symptoms. For example:

  • Enhancing the activity of sodium-potassium pumps.
  • Reducing sodium and calcium overload.

2. Supporting Mitochondrial Function

Treatments designed to improve mitochondrial health—such as antioxidants, metabolic boosters, or therapies targeting oxidative stress—may mitigate energy deficits and reduce fatigue.

3. Improving Blood Flow and Oxygen Delivery

Strategies to address hypoperfusion (reduced blood flow) could reduce reliance on anaerobic metabolism during exertion, preventing sodium buildup and calcium overload.

4. Exercise Caution

While physical activity is essential for overall health, ME/CFS patients must avoid overexertion. Graded exercise therapy (GET), once widely recommended, has been shown to harm many patients and should only be used with caution and under close medical supervision.

Conclusion

Skeletal muscle pathophysiology plays a central role in the symptoms of ME/CFS, including fatigue, exertional intolerance, and PEM. The combination of mitochondrial dysfunction and ionic imbalances creates a vicious cycle of energy deficits and muscle damage. These same mechanisms may underlie the development of PC-ME/CFS in a subset of post-COVID syndrome patients.

Future research should focus on understanding the molecular drivers of skeletal muscle dysfunction in both ME/CFS and PC-ME/CFS. By targeting these underlying mechanisms, we can develop effective treatments to improve the quality of life for millions of individuals suffering from these debilitating conditions.

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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