July 25, 2024

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Unraveling the Biological Basis of Persistent Fatigue in Long COVID

Unraveling the Biological Basis of Persistent Fatigue in Long COVID

Unraveling the Biological Basis of Persistent Fatigue in Long COVID

Feeling Fatigued After COVID-19? Latest Research in Nature Subjournal Reveals Reasons

After contracting COVID-19, many individuals are experiencing post-infection symptoms, commonly referred to as “long COVID.”

The World Health Organization defines this as the persistence of symptoms for at least two months, occurring three months after COVID-19 infection, with no alternative explanation. Symptoms include fatigue, shortness of breath, chest pain, and loss of taste and smell.

However, evidence explaining the occurrence of “long COVID” and how to treat or alleviate post-COVID symptoms is still lacking.

On January 4, 2024, a research team from the University of Amsterdam published a study titled “Muscle abnormalities worsen after post-exertional malaise in long COVID” in the Nature Communications journal, uncovering potential mechanisms behind the persistent fatigue in “long COVID” patients, specifically a reduced energy production in mitochondria within muscle cells.

Unraveling the Biological Basis of Persistent Fatigue in Long COVID: Insights from Mitochondrial Dysfunction and Muscle Abnormalities

Research Highlights:

The study involved 25 “long COVID” patients and 21 healthy control participants. They were subjected to a 15-minute cycling test, causing a prolonged deterioration of symptoms known as post-exertional malaise (PEM). Blood and muscle tissue were observed one week before and one day after the cycling test.

Despite variations among patients, long COVID sufferers exhibited significantly lower maximal oxygen consumption (V̇O2max) and peak power output during exercise compared to the control group. The cardiovascular system of long COVID patients was unaffected, suggesting that cardiovascular issues couldn’t explain the reduced exercise capacity. Parameters like maximal oxygen pulse, gas exchange threshold, and peripheral oxygen extraction indicated dysfunction in the peripheral skeletal muscle during exercise.

The researchers further assessed the structure and function of skeletal muscles to explain the diminished exercise capacity. Long COVID patients showed a higher proportion of highly fatiguable glycolytic fibers in the quadriceps muscle compared to healthy controls, especially in females. The study suggested that changes in intrinsic muscle strength and fatigue characteristics contribute to the reduced exercise performance of long COVID patients, even for the same muscle size.

While succinate dehydrogenase (SDH) activity (a marker of mitochondrial content) correlated with maximal oxygen consumption in healthy controls, this relationship was not observed in long COVID patients. Lower oxidative phosphorylation capacity suggested a reduction in mitochondrial respiratory quality rather than a decrease in enzyme activity.

These findings indicate that the diminished exercise capacity in long COVID patients is associated with a higher proportion of fatiguable glycolytic fibers and lower mitochondrial function.

Metabolic Dysfunction and Post-Exertional Malaise:

To assess whether metabolic and mitochondrial dysfunction is related to post-exertional malaise, the researchers measured mitochondrial respiration and metabolic markers in skeletal muscles before and one day after exercise. Oxidative phosphorylation capacity decreased in both healthy controls and long COVID patients after maximal exercise. However, SDH activity decreased in long COVID patients but not in the healthy control group, suggesting reduced mitochondrial respiratory capacity and content contribute to post-exertional fatigue.

To understand skeletal muscle metabolism during rest and post-exertional fatigue, the researchers analyzed 116 metabolites in skeletal muscles and 83 metabolites in venous blood. Long COVID patients exhibited lower levels of tricarboxylic acid (TCA) cycle metabolites in both muscle and blood, but these levels did not change during post-exertional fatigue. Glucose metabolism in venous blood was higher in long COVID patients at baseline but decreased one week later.

Muscle Damage Induced by Exercise in Long COVID Patients:

To further elucidate the pathophysiology of muscle weakness, fatigue, and pain experienced by long COVID patients after exercise, the researchers sought to identify specific pathological features in skeletal muscles before and after inducing post-exertional fatigue. They found that a significant proportion of long COVID patients exhibited small atrophic fibers and focal necrosis in their skeletal muscles, particularly after exercise, indicating aggravated tissue damage responses.

Both groups showed acute regenerating fibers with central nuclei and alkaline cytoplasm in muscle biopsies, suggesting ongoing muscle regeneration. These results suggest that exercise-induced muscle damage and subsequent regeneration are associated with the pathophysiology of post-exertional fatigue and may explain the muscle pain, fatigue, and weakness experienced by long COVID patients after exercise.

Presence of SARS-CoV-2 Nucleocapsid Protein in Skeletal Muscles:

To determine whether virus remnants were present in skeletal muscles during exercise-induced fatigue in long COVID patients, the researchers stained all muscle slices for the SARS-CoV-2 nucleocapsid protein. They found that almost all long COVID patients and healthy controls exhibited the presence of the SARS-CoV-2 nucleocapsid protein, with no significant difference in protein levels between the two groups. This suggests that the residual presence of the SARS-CoV-2 nucleocapsid protein is similar in long COVID patients and healthy controls and cannot explain the limited exercise capacity or the development of post-exertional fatigue in long COVID patients.


This study aimed to dissect the pathophysiology of reduced exercise capacity and post-exertional fatigue in long COVID patients. The researchers found significant changes in the muscles of long COVID patients, with reduced energy production in mitochondria, often referred to as the cell’s energy factories. Following strenuous exercise, signs of reduced mitochondrial enzyme activity and muscle tissue damage in skeletal muscles were observed. Overall, these findings contribute to understanding the potential physiological mechanisms behind fatigue and limited exercise capacity in long COVID patients.

Corresponding author Rob C. I. Wüst noted, “We observed various abnormalities in the muscle tissue of long COVID patients. At the cellular level, the function of the muscles’ mitochondria, also known as the cell’s energy factories, is impaired, resulting in reduced energy production.”

Another corresponding author, Michèle van Vugt, added, “So, the cause of fatigue is actually biological; the brain needs energy to think, and the muscles need energy to move. This finding implies that we can start exploring treatment methods for long COVID patients.”

Unraveling the Biological Basis of Persistent Fatigue in Long COVID

Reference: https://doi.org/10.1038/s41467-023-44432-3

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