Researchers have just discovered a process that links inflammation and motor dysfunction in fruit flies, providing researchers with a potential target for treating the persistent muscle fatigue that accompanies many infections.
Of the many symptoms of Long COVID, exercise intolerance is thought to be one of the most debilitating.
“This isn’t just a matter of not wanting to move because you feel unwell,” says Aaron Johnson, a developmental biologist at the University of Washington. “These processes reduce the energy levels of your skeletal muscles, reducing their ability to move and function normally.”
Each new outbreak of the SARS-CoV-2 virus increases the risk of long-term COVID-19. Currently, approximately 18 million American adults are experiencing this prolonged illness and the debilitating physical symptoms that accompany it.
Many of these symptoms are familiar, including the lack of energy experienced by about half of long COVID patients. Muscle fatigue is also seen in other post-viral conditions and in people with neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
What all these conditions have in common is inflammation of the central nervous system. Chemical markers associated with brain damage have also been identified in COVID patients.
So developmental biologist Shuo Yang of the University of Washington and his colleagues used animal models to explore how inflamed neurons cause muscle dysfunction. In both flies and mice, they identified a signaling pathway between brain cells and muscles that leads to loss of muscle function.
“Flies and mice with COVID-related proteins in their brains had impaired motor function — the flies couldn’t perform as well as they should and the mice couldn’t run as well or at all as the control mice,” Johnson explains.
“We saw a similar effect on muscle function when the brain was exposed to bacteria-associated proteins and the Alzheimer’s protein amyloid-beta, and we also saw evidence that this effect can be chronic: even if the infection is quickly cleared, the decline in muscle performance in our experiments persisted for several days.”
In humans, inflammation causes neurons to release the immune cytokine interleukin-6 (IL-6). In lab animals, the team found that a similar protein travels through the bloodstream to muscles and activates a cellular program called JAK-STAT, which then reduces the amount of energy produced by the muscle tissue’s mitochondrial power plants.
“It’s unclear why the brain produces protein signals that are so detrimental to muscle function across a range of disease categories,” Johnson says.
“If we want to speculate as to why this process has persisted in us throughout human evolution, despite the damage it causes, it could be that it is the brain’s way of reallocating resources to itself when fighting disease. Further research is needed to better understand this process and its effects on the whole body.”
Yan and team They then used a drug that blocks this pathway in flies and found they could reverse the process, as shown in previous mouse studies. IL-6 inhibitors are already used effectively to treat autoimmune diseases such as rheumatoid arthritis and have so far proven effective in several severe COVID-19 cases.
“It appears likely that the brain-muscle system is activated by respiratory infections via the cerebrospinal fluid (CSF) and continues to signal long after the initial infection has cleared,” the researchers wrote in the paper. “Thus, long COVID may be driven by chronic cytokine signaling.”
The researchers caution that some parts of the puzzle, such as how SARS-CoV-2 enters the human central nervous system and causes this inflammation, are still unknown, but this new information could lead to much-needed relief for people suffering from a variety of chronic diseases.
By altering the chemicals secreted by neurons, the study sheds light on how brain inflammation caused by a variety of conditions can have such profound physical effects on the entire body.
The study is published in Science Immunology.
