Long COVID Muscle Fatigue Linked to Brain Inflammation

Long COVID and post-infection muscle fatigue

Scientists have identified a mechanism in fruit flies that connects inflammation with reduced motor ability, potentially offering a treatment target for the lasting muscle fatigue that can follow many infections.

Among long COVID's many symptoms, difficulty tolerating physical exertion is arguably one of the most disabling.

"This is more than a lack of motivation to move because we don't feel well," says Washington University developmental biologist Aaron Johnson. "These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally."

Each further infection with the SARS-CoV-2 virus raises the likelihood of developing long COVID. Nearly 18 million adults in the United States have experienced this prolonged ill health and its draining physical effects.

Several of these effects are widely recognised, including the discouraging loss of energy experienced by roughly half of people with long COVID. Muscle fatigue also occurs in other post-viral illnesses and among people with neurodegenerative conditions such as Alzheimer's and Parkinson's.

How central nervous system inflammation affects muscles

Inflammation within the central nervous system is the feature shared by all of these conditions. COVID patients have also been found to have chemical markers linked with brain injury.

Washington University developmental biologist Shuo Yang and fellow researchers therefore used animal models to investigate how inflamed neurons may cause muscles to malfunction. In flies and mice, they found a signalling pathway connecting brain cells and muscles that results in declining muscle function.

"Flies and mice that had COVID-associated proteins in the brain showed reduced motor function – the flies didn't climb as well as they should have, and the mice didn't run as well or as much as control mice," explains Johnson.

"We saw similar effects on muscle function when the brain was exposed to bacterial-associated proteins and the Alzheimer's protein amyloid beta. We also see evidence that this effect can become chronic. Even if an infection is cleared quickly, the reduced muscle performance remains many days longer in our experiments."

In people, inflammation prompts neurons to release the immune cytokine interleukin-6 (IL-6). The researchers discovered that an equivalent protein in their animal models travelled through the bloodstream to the muscles, where it switched on a cellular programme known as JAK-STAT. JAK-STAT subsequently reduced the energy generated by mitochondria, the power plants of muscle tissue.

"We're not sure why the brain produces a protein signal that is so damaging to muscle function across so many different disease categories," says Johnson.

"If we want to speculate about possible reasons this process has stayed with us over the course of human evolution, despite the damage it does, it could be a way for the brain to reallocate resources to itself as it fights off disease. We need more research to better understand this process and its consequences throughout the body."

Blocking the brain-muscle signalling pathway

Yang's team then used medicines to block this pathway in flies, confirming that the process could be reversed, as earlier mouse research had indicated. IL-6 inhibitors are already used successfully for autoimmune illnesses including rheumatoid arthritis, and have so far shown promise in a small number of severe COVID-19 cases.

"It seems likely that the brain-muscle axis is activated by respiratory infections via the CSF [cerebrospinal fluid]… and continues to signal long after the initial infection is cleared," the researchers write in their paper. "Long-COVID may therefore be caused by chronic cytokine signaling."

The scientists stress that aspects of the puzzle are still unresolved, including how SARS-CoV-2 enters the human central nervous system and initiates this inflammation. Nevertheless, these findings could provide badly needed relief for people living with a variety of chronic conditions.

It is now evident that changing the chemicals secreted by neurons can explain how brain inflammation from numerous conditions can exert such a major physical effect throughout the body.

The research was published in Science Immunology.