The Secret Behind Muscle Fatigue Associated With Long Covid

Patients with encephalitis, a neurodegenerative disease, often develop "mysterious" muscle problems that appear to be independent of the central nervous system, health experts have revealed.

Now, researchers at Washington University School of Medicine in St. Louis have revealed that encephalitis releases a specific protein that travels from the brain to the muscles and causes them to deteriorate in function.

The study, conducted in fruit flies and mice, identified ways to block this process, which could have implications for treating or preventing muscle wasting sometimes associated with inflammatory diseases, including bacterial infections, Alzheimer's disease and "long Covid".

“We are interested in understanding the profound muscle fatigue associated with some common diseases,” said lead researcher Aaron Johnson, associate professor of developmental biology. “Our study suggests that when we get sick, proteins sent from the brain travel through the bloodstream and reduce energy levels in skeletal muscle.”

The researchers modeled three different types of diseases: bacterial infection with E. coli, viral infection with SARS-CoV-2, and Alzheimer's disease.

When the brain is exposed to the inflammatory proteins characteristic of these diseases, harmful chemicals called reactive oxygen species build up, which trigger brain cells to produce an immune-related molecule called interleukin 6 (IL-6), which travels throughout the body via the bloodstream.

The researchers found that IL-6 reduced energy production in the mice's muscle mitochondria (the cells' energy factories).

“Flies and mice with COVID-19-associated proteins in their brains showed reduced motor function,” Johnson said. “We saw similar effects on muscle function when the brain was exposed to bacteria-associated proteins and the Alzheimer’s protein amyloid beta. We also see evidence that this effect can become chronic.”

The researchers stress that the same processes are likely to be relevant to humans. Bacterial meningitis in the brain is known to increase levels of IL-6, and could be linked to muscle problems in some patients, for example.

Many long-Covid patients also complain of extreme fatigue and muscle weakness, even long after the initial infection has resolved. Alzheimer’s patients show increased levels of interleukin-6 in the blood, in addition to muscle weakness.

“We’re not sure why the brain produces a protein signal that impairs muscle function in so many different categories of diseases,” Johnson said. “If we were to speculate about why this process might have stayed with us throughout human evolution, it might be a way for the brain to reallocate resources to itself while fighting disease.”

The study was published in the journal Science Immunology.