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"Recent studies have found that in addition to neural/hormonal regulation, different organs can achieve mutual regulation through metabolic small molecules and non-hormonal secretory proteins. This regulatory mechanism is called inter-organ communication networks (ICN). ICN can actively/passively respond to a variety of pathological changes, participate in regulating and maintaining the normal physiological functions and overall homeostasis of the body's organs. For example, ICN abnormalities are closely related to the occurrence of a variety of diseases such as valvular heart disease, non-alcoholic fatty liver disease, and chronic nephritis."

"We are currently conducting research to see if exercise can induce the secretion of certain myokines, which can enter the circulatory system, penetrate the blood-brain barrier, and thus inhibit the occurrence of Alzheimer's disease."

Like other tissues and organs in the human body, brain nerves can also become "inflamed". Bacteria, viruses and even aging can trigger a response from the immune system, leading to inflammation of the brain nerves and, in turn, neurological degeneration. Scientists have found that many encephalitis diseases are often accompanied by a decline in muscle function, but the relationship between them is not yet clear.

Recently, a new study revealed the deep connection between neuroinflammation and muscle function degeneration. The study, titled "Infection and Chronic Disease Activate a Systemic Brain-muscle Signaling Axis", was published in the journal Science Immunology on July 12, 2024. The author is Yang Shuo's team from the School of Life Sciences of Fudan University.

By studying the neuroinflammation and muscle degeneration caused by Escherichia coli, the new coronavirus (SARS-CoV-2), and Alzheimer's disease (AD) in fruit fly and mouse models, the study found that all these diseases activated a "brain-muscle signaling axis" that regulates muscle performance, in which multiple stress factors such as inflammation lead to the activation of Upd3 (Unpaired3)/IL-6 (interleukin-6) cytokines, and further activate the JAK-STAT signaling pathway (Janus kinase-signal transducer and activator of transcription) in skeletal muscle, regulating mitochondrial function and ultimately affecting muscle function.

"Cytokines" are a class of small molecule proteins that act like "messengers" and convey "commands" by binding to cell surface receptors to promote or inhibit cell differentiation, proliferation and other behaviors. "Organs communicate by secreting molecules, which enter the circulatory system and transfer to target tissues, leading to a variety of consequences including immunity, behavior, neurogenesis, cardiovascular function, and cell aging," the study wrote.

It is generally believed that changes in nerve function caused by neuroinflammation directly lead to external symptoms such as decreased muscle function, but this study reveals another universal mechanism from the perspective of inter-organ communication.

The traditional view (left) is that neuroinflammation caused by infection produces inflammatory factors, leading to neuronal apoptosis, which directly affects muscle control. This study (right) discovered a mechanism by which the brain and muscles communicate through cytokines to regulate muscle function. Photo provided by the interviewee.

How did the researchers conduct their research using fruit fly and mouse models? Is the muscle function decline caused by bacteria, viruses, and neurodegenerative diseases such as Alzheimer's disease essentially the same? Can this decline be reversed? What is the significance of this research for the treatment of brain/muscle diseases? In order to answer these questions, The Paper recently interviewed Yang Shuo, the first author of the study and a researcher at the School of Life Sciences at Fudan University.

【dialogue】

Pengpai Technology:Could you please introduce yourself and your team? What inspired you to conduct this research?

Yang Shuo (Research Project Leader and Doctoral Supervisor, School of Life Sciences, Fudan University):I joined the School of Life Sciences at Fudan University in February 2023. My research focuses on cross-organ signal transmission, muscle morphogenesis, and genetic diseases of the motor system. I have published several papers as the first author and corresponding author in journals such as Cell Host & Microbe, Science Immunology, Nature Communications, Development, and JCI insight (italics). The laboratory currently focuses on three directions: first, exploring the functions and mechanisms of multi-organ interaction networks in overall homeostasis; second, screening for exercise protective factors against Alzheimer's disease; and third, establishing animal models of genetic diseases related to the motor system.

When I was a postdoctoral fellow at the University of Washington, my co-supervisor, Professor Aaron Johnson, and I had been focusing on the developmental mechanisms of the muscle system and related myopathies. During the COVID-19 epidemic, in early 2021, we found that our colleagues often had neurological symptoms such as anxiety and muscle system symptoms such as muscle weakness after recovering from the new crown. This matter aroused our interest.

We found that patients with a variety of diseases, including bacterial encephalitis, viral encephalitis, and neurodegenerative diseases, all showed dual brain/muscle symptoms. In 2020, our research just published in the classic journal Development in developmental biology showed that the ectoderm (which develops into epidermis and nervous tissue, etc.) can regulate the balance of the FGF pathway in mesoderm (which develops into muscle) muscle cells by secreting ligands of the FGF signaling pathway, thereby manipulating morphogenesis and organ construction. Therefore, we speculate that, similarly, will encephalitis change the secretory profile of the brain, thereby directly regulating the physiological function of muscles through secreted proteins?

Just like Atlas, the god of the sky in Greek mythology, holding up the sky, neuritis makes people's muscles overwhelmed. Photo provided by the interviewee.

Pengpai Technology:What is neuroinflammation? Since inflammation is caused by the immune system's "protection" of the body, why does it cause harm to the body?

Yang Shuo:Fighting external infection is the core function of the immune system. The immune system can respond to infection in many ways, such as phagocytizing pathogens, releasing inflammatory factors to kill pathogens, and producing antibodies to prevent pathogens from invading cells. However, overactivation of the immune system will cause the massive release of inflammatory factors such as interleukins, TNF-a, and complement protein molecules, and launch a stormy suicide attack on the source of infection and infected cells, causing bystander damage to the body's own tissue cells accompanied by increased vascular permeability and circulatory disorders, and even leading to multiple organ failure (MOF). The cause of death of many severe COVID-19 patients stems from this. Therefore, controlled activation and inhibition of the immune system is an inevitable requirement for the human body to maintain normal function.

Pengpai Technology:What is inter-organ communication? In recent decades, some similar perspectives have emerged in biology, such as the "brain-gut axis". Can you introduce the background and development of this idea?

Yang Shuo:The development from single-celled animals to multi-celled animals is a leap in the history of animal evolution. Starting from multi-celled animals, the various parts of the animal body gradually differentiated into organs with specific functions in order to adapt to the external environment. Classical theory holds that the functions of various organs are regulated by the endocrine system and the nervous system.

In recent years, studies have found that in addition to neural/hormonal regulation, different organs can achieve mutual regulation through metabolic small molecules and non-hormonal secretory proteins. This regulatory mechanism is called inter-organ signal transmission (ICN). ICN can actively/passively respond to a variety of pathological changes, participate in the regulation and maintenance of the normal physiological functions and overall homeostasis of the body's organs. For example, ICN abnormalities are closely related to the occurrence of a variety of diseases such as valvular heart disease, non-alcoholic fatty liver disease, and chronic nephritis.

At present, in addition to the "brain-gut axis", the organ communication that has received special attention is the communication between the brain and muscle cells. On July 22, Cell published a study titled Innate immune memory after brain injury drives inflammatory cardiac dysfunction, and on July 12, Nature Cardiovascular Research published a study titled Reward system activation improves recovery from acute myocardial infarction, both of which showed the regulatory effect of the brain on the heart. On May 3, Science published a study titled Brain-muscle communication prevents muscle aging by maintaining daily physiology, showing that the central nervous system biological clock can regulate skeletal muscle function in unknown ways.

Therefore, further analysis of ICN can not only enhance our understanding of the regulatory network between organs in living organisms, but also provide a basis for interventional treatment of ICN-related diseases such as systemic inflammatory storms, nerve damage, and muscle weakness.

Pengpai Technology:The article explores the brain-muscle communication mechanism caused by neuroinflammation caused by E. coli, the new coronavirus, and Alzheimer's disease. Why were these three cases chosen?

Yang Shuo:Because we found from daily life and literature search that these three conditions cover the vast majority of people with dual brain/muscle disorders that we come into contact with.

Pengpai Technology:The study mainly selected Drosophila melanogaster as a model to study brain-to-muscle communication. How are these models constructed? Can fruit flies also "get" COVID-19 and Alzheimer's? What are the similarities and differences between insect muscle function regulation and human muscle function regulation? The mouse model was also used in the study. What are the considerations?

Yang Shuo:Fruit flies cannot develop Alzheimer's. There are many explanations for the causes of Alzheimer's disease, but most people accept the amyloid beta and tau protein theories, which are caused by abnormal accumulation of these proteins in the brain. Therefore, in animal models, we generally construct Alzheimer's disease models by expressing human amyloid beta 42 protein in the brain.

The novel coronavirus invades cells by binding to the ACE2 receptor. Although fruit flies have homologous proteins of the ACE2 receptor (Nature, 2002 Jun 20;417(6891):822-8), the novel coronavirus cannot directly infect fruit fly cells. Therefore, we use genetic methods to specifically express the virulence proteins of the novel coronavirus, such as NSP1, in fruit flies to explore the effects of the virulence proteins of the virus on the body. The advantage of this research method is that it can use the rich genetic tools of fruit flies to speed up the research progress.

Insects, like humans, have skeletal muscles, smooth muscles, and cardiac muscles. Their muscle systems are highly conserved with those of humans at the molecular and cellular levels, making them good model animals for studying muscle system development, function, and related diseases.

The reason why we use the mouse model is that insects are not mammals after all, and there is a big gap between them and humans. Therefore, verifying the findings in fruit flies in mice, which are also mammals, is necessary to prove the species conservation of this study.

Pengpai Technology:The study found a signaling pattern in all three types of neuroinflammation, in which the extracellular ligand Upd3 responded to reactive oxygen species in the central nervous system and induced skeletal muscle JAK-STAT signaling, leading to mitochondrial dysfunction and reduced motor function. Can you explain this process to us in layman's terms?

Yang Shuo:Mitochondria are the core of energy metabolism, and muscles are the biggest energy consumers. Mitochondrial dysfunction will inevitably lead to reduced energy production, so muscles will lack energy supply and cannot function normally.

Pengpai Technology:In human patients, the motor dysfunction caused by these three diseases seems to manifest differently. Is the mechanism discovered in this study exactly the same in all three diseases? Is it the main cause of the muscle loss in these diseases?

Yang Shuo:From a cell biology perspective, all three diseases cause disease by affecting the membrane potential of muscle mitochondria, so their pathogenic mechanisms are exactly the same.

We are currently unable to give a conclusion on whether it is the main cause of muscle dysfunction. We can only prove that it plays an important role in muscle dysfunction, but we cannot give a conclusion on how much it accounts for.

Pengpai Technology:Is the muscle loss caused by this process reversible? Will it disappear after the disease is cured?

Yang Shuo:Yes, our experiments have shown that the decline is reversible and the muscles will gradually recover normal function.

Pengpai Technology:Long covid is a topic of concern to many people. What has the research found? Is cognitive decline and motor function decline an inevitable result?

Yang Shuo:We found that neurological infection is one of the causes of contracting COVID-19. But the dual brain/muscle disease does not occur in every patient.

Pengpai Technology:In some studies on the gut-brain axis, people have found that regulating the composition of the microbiota can in turn affect the nervous system. Do you think the brain-muscle axis presented in this study may be bidirectional?

Yang Shuo:This is a good question. We are currently studying whether exercise can induce the secretion of certain muscle factors, which can enter the circulatory system and penetrate the blood-brain barrier, thereby inhibiting the occurrence of Alzheimer's disease. Currently, irisin is the most popular muscle-derived neuroprotective protein, but because it affects metabolism, many problems have arisen in its application. We want to screen more exercise protective factors through genetic models, so as to artificially simulate the effects of exercise, delay the onset of Alzheimer's disease, and alleviate its progression.

Pengpai Technology:What are the prospects for this research in drug development and disease diagnosis and treatment?

Yang Shuo:There are already many neutralizing antibodies and related pathway inhibitors targeting the Upd3/IL-6 molecule we found on the market. Therefore, our research provides a scientific basis for expanding the indications of these drugs.

Original information:

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. July 12, 2024.

https://www.science.org/stoken/author-tokens/ST-1985/full