Summary: A new study reveals how brain inflammation from infections and neurodegenerative diseases causes muscle weakness by releasing the protein IL-6. The researchers found that IL-6 travels from the brain to the muscles, reducing their energy production and function.
This discovery could lead to treatments for muscle degeneration in diseases such as Alzheimer’s and long Covid. Blocking the IL-6 pathway could prevent muscle weakness associated with brain inflammation.
Highlights:
- IL-6 Protein: Released by the brain during inflammation, causing muscle weakness.
- Reduction of energy consumption: IL-6 reduces energy production in muscle mitochondria.
- Treatment potential: Blocking the IL-6 pathway could prevent muscle weakness in various diseases.
Source: WUSTL
Infections and neurodegenerative diseases cause inflammation in the brain. But for unknown reasons, patients with brain inflammation often develop muscle problems that appear to be independent of the central nervous system.
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 loss of muscle function.
The study, conducted in fruit flies and mice, also 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.
The study is published July 12 in the journal Scientific immunology.
“We want to understand the very profound muscle fatigue associated with some common diseases,” said lead author Aaron Johnson, PhD, associate professor of developmental biology.
“Our study suggests that when we get sick, messenger proteins from the brain circulate in the bloodstream and reduce energy levels in skeletal muscle. It’s not just a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, thereby decreasing the ability to move and function normally.”
To study the effects of brain inflammation on muscle function, the researchers modeled three different types of disease: a E. coli Bacterial infection, SARS-CoV-2 viral infection, and Alzheimer’s disease. When the brain is exposed to inflammatory proteins characteristic of these diseases, harmful chemicals called reactive oxygen species accumulate.
Reactive oxygen species prompt brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which circulates throughout the body via the bloodstream. The researchers found that IL-6 in mice, and the corresponding protein in fruit flies, reduced energy production in muscle mitochondria, the cells’ energy factories.
“Flies and mice that had COVID-associated proteins in their brains 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,” Johnson said.
“We observed similar effects on muscle function when the brain was exposed to proteins associated with bacteria and the Alzheimer’s disease protein amyloid beta. We also found that this effect can become chronic. Even if an infection clears quickly, the decrease in muscle performance persists for several days longer in our experiments.”
Johnson, along with collaborators at the University of Florida and first author Shuo Yang, Ph.D. — who did this work as a postdoctoral researcher in Johnson’s lab — argue that the same processes are likely relevant in humans. Meningitis, a bacterial brain infection, is known to increase IL-6 levels and may be associated with muscle problems in some patients, for example.
Among COVID-19 patients, SARS-CoV-2 inflammatory proteins have been detected in the brain at autopsy, and many long-COVID patients report extreme fatigue and muscle weakness even long after the initial infection has passed. Alzheimer’s patients also have increased blood levels of IL-6 and muscle weakness.
The study identifies potential targets to prevent or treat muscle weakness related to brain inflammation. The researchers found that IL-6 activates what is called the JAK-STAT pathway in muscles, which causes mitochondria to reduce energy production.
Several treatments already approved by the Food and Drug Administration for other diseases can block this pathway. JAK inhibitors as well as several monoclonal antibodies against IL-6 are approved to treat various types of arthritis and manage other inflammatory diseases.
“We don’t know exactly why the brain produces a protein signal that is so damaging to muscle function in so many different disease categories,” Johnson said.
“If we want to speculate about possible reasons why this process has persisted throughout human evolution, despite the damage it causes, it could be a way for the brain to reallocate resources to itself as it fights disease. We need to do more research to better understand this process and its consequences throughout the body.
“In the meantime, we hope our study will encourage further clinical research into this pathway and determine whether existing treatments that block various parts of it can help the many patients who suffer from this type of debilitating muscle fatigue,” he said.
Yang S, Tian M, Dai Y, Wang R, Yamada S, Feng S, Wang Y, Chhangani D, Ou T, Li W, Guo X, McAdow J, Rincon-Limas DE, Yin X, Tai W, Cheng G, Johnson A. Infection and chronic disease activate a systemic brain-muscle signaling axis that regulates muscle function. Science Immunology. 2024 Jul 12.
Funding: This work is supported by the National Institutes of Health (NIH), grant numbers R01 AR070299 and R01AG059871; the National Key Research and Development Plan of China, grant numbers 2021YFC2302405, 2021YFC2300200, 2022YFC2303200, 2022YFC2303400, and 2022YFE0140700; the National Natural Science Foundation of China, grant numbers 32188101, 82271872, 32100755, 32172940, and 82341046; the Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases, grant number SZSM202211023; Yunnan Provincial Science and Technology Project to Southwest United Graduate School, Grant No. 202302AO370010; New Cornerstone Science Foundation through the New Cornerstone Investigator Program; Xplorer Award of Tencent Foundation; Natural Science Foundation of Heilongjiang Province, Grant No. JQ2021C005; Distinguished Young Scholars Science Fund Program (Overseas); and Shenzhen Bay Laboratory Startup Fund, Grant No. 2133011.
About this news on neuroinflammation and neurology research
Author: Jessica Church
Source: WUSTL
Contact: Jessica Church – WUSTL
Picture: Image credited to Neuroscience News
Original research: Access closed.
“Infection and chronic disease activate a systemic brain-muscle signaling axis” by Aaron Johnson et al. Sciences Immunology
Abstract
Infection and chronic disease activate a systemic brain-muscle signaling axis
Infections and neurodegenerative diseases cause neuroinflammation, but affected individuals often experience non-neurological symptoms, including muscle pain and fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood.
We have developed several models to study the impact of CNS stressors on motor function and found that Escherichia coli SARS-CoV-2 infections and protein expression caused accumulation of reactive oxygen species (ROS) in the brain. ROS induced the expression of cytokine Unpaired 3 (Upd3) in Drosophila and its homologue, IL-6, in mice.
CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, leading to muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expression of toxic amyloid-β (Aβ42) in the CNS.
Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.