A new study sheds light on how exercise boosts brain function by exploring the role of nerves in muscle-brain communication. The study, published in the Proceedings of the National Academy of Sciences, reveals that muscles release molecules that support brain cell communication and development, and this release is driven in part by signals from the nerves that tell muscles to move. These findings help clarify the complex relationship between exercise, muscle function, and brain health.
Previous research has established that when muscles are engaged during physical activity, they release molecules that travel through the bloodstream and positively affect brain cells. These molecules, such as hormones and small vesicles containing RNA, help brain cells form stronger connections and communicate more efficiently.
However, the role of the nerves that trigger muscle movement in this process was not well understood. With age, or due to injury and disease, people tend to lose nerve connections to their muscles. This decline in nerve supply can lead to muscle breakdown and contribute to broader organ dysfunction, including in the brain.
The researchers aimed to investigate how nerve signals to muscles influence the release of molecules that support brain function. They hoped to better understand the mechanisms of this muscle-brain communication and identify ways to preserve or enhance this connection, particularly for older adults or those with neuromuscular diseases. If successful, their findings could provide a foundation for developing treatments that target muscle-brain interactions, potentially helping people maintain cognitive function even as they lose muscle mass and nerve connections.
To explore the role of nerve signals in muscle-brain communication, the researchers created two different models of muscle tissue: one that included nerve cells, and one that did not. This allowed them to compare the two and determine how the presence of nerves affected the muscle’s ability to release brain-enhancing molecules.
The muscles were placed in a laboratory dish, where one group of tissues received nerve cells, allowing the muscle and nerve cells to form connections similar to what happens in the body. These nerve-muscle connections are known as neuromuscular junctions. The second group of muscle tissues was left without any nerve cells. After establishing these two groups, the researchers stimulated the nerve-connected muscles using glutamate, a neurotransmitter that carries signals in the brain and nervous system, to mimic the kind of stimulation muscles would receive during exercise.
The researchers then measured the amount and types of molecules released by the muscles into the surrounding fluid. They specifically looked at two types of molecules: hormones, like irisin, which are known to have beneficial effects on the brain, and extracellular vesicles, tiny particles that carry RNA and other molecular cargo between cells.
In addition to measuring the overall quantity of molecules, the team also examined the specific types of RNA found within the vesicles, as these RNA fragments can influence brain cell development and communication.
The study revealed several key findings. First, the muscle tissues connected to nerves released significantly more brain-beneficial molecules compared to muscles without nerves. Specifically, the nerve-connected muscles produced higher levels of the hormone irisin, which has been linked to the positive effects of exercise on brain health. Irisin has been shown to support brain function by crossing the blood-brain barrier and promoting neurogenesis, the process by which new brain cells are formed.
Furthermore, the nerve-connected muscles also released a greater variety of extracellular vesicles, which carried RNA fragments associated with brain development and neuron communication. These vesicles are particularly important because they can transport molecular signals that help brain cells form stronger connections and communicate more effectively.
When the researchers stimulated the nerve-connected muscles with glutamate, they saw an even larger increase in the release of irisin and extracellular vesicles. The RNA fragments found in the vesicles were more diverse in this stimulated group, suggesting that the nerve signals to muscles not only increase the quantity of molecules released but also enhance the complexity of the molecular cargo, making it more beneficial for brain function.
These findings highlight the crucial role that nerve signals play in promoting muscle-brain communication. As muscles lose their nerve connections with age or due to injury, their ability to release these brain-supporting molecules diminishes, potentially contributing to cognitive decline and other brain-related issues.
Although this study provided new insights into the role of nerves in muscle-brain communication, it had some limitations. First, the experiments were conducted using lab-grown muscle tissues, which, while helpful for isolating certain factors, do not fully replicate the complex environment of a living organism. Future studies will need to test whether these findings hold true in living animals and eventually in humans.
Moving forward, the researchers plan to investigate the precise mechanisms at the junction between nerves and muscle cells. They hope to determine whether nerve impulses directly affect the production of brain-boosting factors or primarily regulate their release. This knowledge could help inform the development of targeted therapies for people with neuromuscular diseases or age-related muscle loss.
The team also aims to use their laboratory muscle models as platforms for efficiently producing brain-beneficial molecules. By simulating exercise in a lab setting, they hope to better understand how to enhance the release of these molecules, potentially paving the way for new treatments that mimic the benefits of exercise for people who are unable to engage in physical activity due to injury or disease.
The study, “Neuronal innervation regulates the secretion of neurotrophic myokines and exosomes from skeletal muscle,” was authored by Kai-Yu Huang, Gaurav Upadhyay, Yujin Ahn, Masayoshoi Sakakura, Gelson J. Pagan-Diaz, Younghak Cho, Amanda C. Weiss, Chen Huang, Jennifer W. Mitchell, Jiahui Li, Yanqi Tan, Yu-Heng Deng, Austin Ellis-Mohr, Zhi Dou, Xiaotain Zhang, Sehong Kang, Qian Chen, Jonathan V. Sweedler, Sung Gap Im, Rashid Bashir, Hee Jung Chung, Gabriel Popescu, Martha U. Gillette, Mattia Gazzola, and Hyunjoon Kong.
