summary: A new study uncovers how inflammation in the brain caused by infection or neurodegenerative disease releases the IL-6 protein, leading to muscle weakness. The researchers found that IL-6 travels from the brain to muscles, where it reduces muscle energy production and function.
This discovery could lead to treatments for muscle wasting in diseases such as Alzheimer’s and long COVID: Blocking the IL-6 pathway may prevent muscle loss associated with brain inflammation.
Key Facts:
- IL-6 Protein: It is released from the brain during inflammation and causes muscle weakness.
- Energy Savings: IL-6 reduces energy production in muscle mitochondria.
- Treatment possibilities: Inhibiting the IL-6 pathway may prevent muscle weakness in a variety of diseases.
sauce: Wüstel
Infections and neurodegenerative diseases cause inflammation in the brain, but for unknown reasons, patients with brain inflammation often develop muscle problems that seem unrelated to the central nervous system.
Now, researchers at Washington University School of Medicine in St. Louis have uncovered how inflammation in the brain releases specific proteins that travel from the brain to muscles, causing loss of muscle function.
The study also identified a way to inhibit this process in fruit flies and mice, which could have implications for treating or preventing muscle wasting that can accompany inflammatory diseases such as bacterial infections, Alzheimer’s disease, and long COVID.
The study was published in the journal Neurology on July 12. Science Immunology.
“We’re interested in understanding the very severe muscle fatigue that’s associated with some common diseases,” said senior author Aaron Johnson, PhD, associate professor of developmental biology.
“Our research suggests that when you get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in your skeletal muscles. This isn’t just because you feel unwell and don’t have the motivation to move; these processes reduce energy levels in your skeletal muscles, reducing their ability to move and function normally.”
To explore the impact of brain inflammation on muscle function, the researchers modeled three different types of the disease. E. coli When the brain is exposed to the inflammatory proteins that characterize diseases such as bacterial infections, SARS-CoV-2 virus infections, and Alzheimer’s disease, harmful chemicals called reactive oxygen species build up.
Reactive oxygen species trigger brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which circulates throughout the body in the bloodstream. The researchers found that mouse IL-6 and its counterpart in fruit flies reduced energy production in muscle mitochondria, the cells’ energy factories.
“Flies and mice with COVID-related proteins in their brains had impaired motor function — the flies couldn’t run as well as they should and the mice couldn’t run as well as the control mice,” Johnson said.
“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 was quickly cleared, the decline in muscle performance in our experiments continued for several days.”
Johnson, along with his collaborators at the University of Florida and lead author Shuo Yang, PhD, who conducted the study as a postdoctoral researcher in Johnson’s lab, argue that the same process is likely relevant in humans: For example, meningitis, a bacterial brain infection, is known to increase IL-6 levels, which may be associated with muscle problems in some patients.
Inflammatory SARS-CoV-2 proteins have been found during autopsies of the brains of COVID-19 patients, and many long COVID patients report extreme fatigue and muscle weakness long after the initial infection has subsided. Patients with Alzheimer’s disease also show elevated levels of IL-6 in their blood and muscle weakness.
This study identifies a potential target for preventing or treating muscle weakness associated with brain inflammation. Researchers found that IL-6 activates a pathway in muscle called the JAK-STAT pathway, which is responsible for reducing mitochondrial energy production.
Several therapeutic drugs already approved by the Food and Drug Administration for other diseases can block this pathway: JAK inhibitors and several monoclonal antibodies against IL-6 have been approved for the treatment of various types of arthritis and for managing other inflammatory diseases.
“It’s unclear why the brain produces protein signals that are so detrimental to muscle function across so many different disease categories,” Johnson said.
“If we want to speculate as to why this process has remained with us throughout human evolution, despite the damage it causes, it could be that it is the brain’s way of reallocating resources to itself as it fights disease. Further research is needed to better understand this process and its effects on the whole body.”
“In the meantime, we hope that our study will spur further clinical research into this pathway and lead to whether existing therapies that block different parts of this pathway could help many patients who suffer from this type of debilitating muscle wasting,” 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 controls muscle function. Science Immunology. 12 July 2024.
Funding: This research was supported by the U.S. National Institutes of Health (NIH) Grant Numbers R01 AR070299 and R01AG059871, National Key Research and Development Program of China Grant Numbers 2021YFC2302405, 2021YFC2300200, 2022YFC2303200, 2022YFC2303400 and 2022YFE0140700, National Natural Science Foundation of China Grant Numbers 32188101, 82271872, 32100755, 32172940 and 82341046, and Shenzhen Sanming Project for Vector-Borne Disease Prevention and Research Grant Number SZSM202211023. Yunnan Science and Technology Project of Southwestern United Graduate School (Grant No. 202302AO370010), New Cornerstone Researcher Program of New Cornerstone Science Foundation, Xplorer Award of Tencent Foundation, Heilongjiang Provincial Natural Science Foundation (Grant No. JQ2021C005), Overseas Outstanding Young Researchers Scientific Fund Program, Shenzhen Bay Research Institute Start-up Fund (Grant No. 2133011), etc.
About this Neuroinflammation and Neurology Research News
author: Jessica Church
sauce: Wüstel
contact: Jessica Church – WUSTL
image: Image courtesy of Neuroscience News
Original Research: The access is closed.
“Infectious and chronic diseases activate the brain-muscle signaling axis throughout the bodyAaron Johnson et al. Science Immunology
Abstract
Infectious and chronic diseases activate the brain-muscle signaling axis throughout the body
Infectious diseases and neurodegenerative diseases cause neuroinflammation, but affected individuals often exhibit non-neurological symptoms such as muscle pain and fatigue. The molecular pathways by which neuroinflammation leads to pathology outside the central nervous system (CNS) are not well understood.
We have developed several models to investigate the effects of central nervous system stressors on motor function. E. coli Infection and expression of SARS-CoV-2 proteins led to the accumulation of reactive oxygen species (ROS) in the brain, which induced the expression of the cytokine unpaired 3 (Upd3) in the brain. Drosophila and its homologous gene, IL-6, were investigated in mice.
CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, leading to muscle mitochondrial dysfunction and motor dysfunction.A similar phenotype was observed after expression of toxic amyloid beta (Aβ42) in the CNS.
Thus, infections and chronic diseases activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome to directly control muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
