New Study Explains How Inflammation Weakens Muscles During Illness

Infections and neurodegenerative diseases cause inflammation in the brain. However, for unknown reasons, patients with brain inflammation often develop muscle problems that seem to be independent of the central nervous system.

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

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

In the study, researchers investigated the effects of brain inflammation on muscle function by modeling three diseases: an E. coli bacterial infection, a SARS-CoV-2 viral infection, and Alzheimer's disease.

They found that brain inflammation caused by these diseases leads to the buildup of reactive oxygen species, which in turn triggers the production of interleukin-6 (IL-6). IL-6 then travels through the bloodstream and reduces energy production in muscle mitochondria. This was observed in both mice and fruit flies.

The study suggested that IL-6 activates the JAK-STAT pathway in muscles, causing decreased mitochondrial function. This pathway can be blocked by existing FDA-approved JAK inhibitors and monoclonal antibodies against IL-6, offering potential treatments for muscle weakness related to brain inflammation.

"We are interested in understanding the very deep muscle fatigue that is associated with some common illnesses. Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle. This is more than a lack of motivation to move because we don't feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally,” said senior author Aaron Johnson, PhD, an associate professor of developmental biology.

“In the study, flies and mice with COVID-associated proteins in their brains exhibited reduced motor function. Flies had difficulty climbing, while mice ran less and with less efficiency compared to controls. Similar muscle function impairments were observed when the brain was exposed to bacterial-associated proteins and the Alzheimer's protein amyloid beta. The researchers noted that these effects could become chronic, with reduced muscle performance persisting long after the initial infection was cleared..”

Reference: Yang, S., et al. (2024) Infection and chronic disease activate a systemic brain-muscle signaling axis; Washington University School of Medicine; Science Immunology. doi.org/10.1126/sciimmunol.adm7908.