Exercise presents advantages at the neuronal level, demonstrating significant chemical and mechanical effects, according to research findings. This could shape the future of exercise-based therapies aimed at mending damaged or deteriorating nerves.
It’s widely acknowledged that exercise is beneficial for the body. Consistent physical activity not only fortifies muscles but also enhances bone strength, improves blood circulation, and boosts the immune system.
Recently, engineers from MIT discovered that exercise can also positively influence individual neurons. They identified that when muscles contract during physical activity, they release a mix of biochemical signals known as myokines. Neurons exposed to these muscle-derived signals exhibited growth rates four times greater than those not influenced by myokines. This cellular research indicates that exercise may have a profound biochemical impact on nerve growth.
Interestingly, the researchers noted that neurons respond to both the biochemical signals and the physical forces of exercise. They found that when neurons are repeatedly stretched, similar to the contraction and relaxation of muscles during exercise, these neurons grow as much as those affected by myokines.
While earlier studies hinted at a biochemical connection between muscle activity and nerve growth, this investigation is the first to suggest that physical factors are equally significant, according to the researchers. The findings, set to be published in the journal Advanced Healthcare Materials, clarify the relationship between muscles and nerves during physical activity and could guide therapies aimed at repairing damaged or weak nerves.
“With the discovery of this muscle-nerve interaction, there’s potential for treatments for issues like nerve injury, where the communication between nerves and muscles has been disrupted,” explains Ritu Raman, the Eugene Bell Career Development Assistant Professor of Mechanical Engineering at MIT. “By stimulating the muscle, we might encourage nerve healing, aiding those who have lost mobility due to traumatic injuries or neurodegenerative conditions.”
Raman, the lead author of the study, collaborated with MIT’s Department of Mechanical Engineering members Angel Bu, Ferdows Afghah, Nicolas Castro, Maheera Bawa, Sonika Kohli, Karina Shah, and Brandon Rios, along with Vincent Butty from the Koch Institute for Integrative Cancer Research.
Muscle Communication
In 2023, Raman and her team demonstrated that they could help restore mobility in mice with severe muscle injuries by first implanting muscle tissue at the injury site, then activating the new tissue through light stimulation. This method led to the restoration of motor functions, putting the mice at activity levels similar to healthy counterparts.
Upon examining the grafted muscle, they noticed regular exercise prompted the muscle to produce specific biochemical signals known to stimulate the growth of nerves and blood vessels.
“It was fascinating because we often assume that nerves are solely responsible for controlling muscles, without considering that muscles can also send signals back to the nerves,” Raman remarks. “This led us to speculate that muscle stimulation might promote nerve growth. However, many other cell types exist, and proving that the nerves grow due to the muscles—rather than the immune system or other factors—can be quite challenging.”
In their latest research, the team aimed to investigate the direct impacts of exercising muscles on nerve growth, concentrating only on muscle and nerve tissues. They cultivated mouse muscle cells into long fibers that combined to form a small sheet of mature muscle tissue, roughly the size of a quarter.
The researchers genetically engineered the muscle to contract in response to light. By flashing a light on the muscle repeatedly, they could simulate exercise. Raman had previously designed a unique gel mat that supports and exercises muscle tissue without allowing it to detach during stimulation.
They then gathered samples from the surrounding solution in which the muscle was exercised, expecting it to contain myokines along with growth factors, RNA, and various proteins.
“You can think of myokines as a biochemical mixture that muscles secrete, some of which may be beneficial for nerves, while others may not influence nerves at all,” Raman explains. “Muscles consistently secrete myokines, but they produce a higher quantity during exercise.”
“Exercise as a Therapeutic Tool”
The researchers transferred the myokine-rich solution to a separate dish containing motor neurons—nerves located in the spinal cord that govern voluntary muscle movements. These neurons were derived from mouse stem cells, also growing on a similar gel mat. After exposure to this myokine mixture, the neurons rapidly began to grow, exhibiting growth rates four times higher than those that did not receive the biochemical solution.
“The growth is significantly swifter and farther, and the effect is almost immediate,” Raman noted.
To further understand how neurons reacted to the exercise-generated myokines, the team performed genetic analyses, extracting RNA from the neurons to determine if the myokines prompted any changes in the expression of particular neuronal genes.
“We found that many of the genes activated in neurons stimulated by exercise not only related to growth but also to the maturation of neurons, their ability to communicate with muscles and other nerves, and developing mature axons,” Raman said. “Exercise appears to influence not just the growth of neurons but also their maturation and functionality.”
The findings imply that the biochemical effects of exercise can aid neuron growth. The team then explored whether the physical exertion alone could yield similar enhancements.
“Neurons are physically linked to muscles, so they stretch and respond as the muscle moves,” Raman points out. “We wanted to see if mechanically stretching the neurons back and forth—simulating exercise—could stimulate their growth, even without biochemical signals from the muscle.”
To test this, the researchers positioned another group of motor neurons on a gel mat embedded with tiny magnets. Using an external magnet, they vibrated the mat and the neurons back and forth, effectively “exercising” the neurons for 30 minutes each day. Surprisingly, they discovered that this mechanical activity stimulated neuron growth to a level comparable to that induced by the myokine treatment, with significant growth observed compared to non-exercised neurons.
“This is promising because it indicates that both biochemical and mechanical effects of exercise are equally essential,” Raman notes.
Having established that exercising muscle can promote nerve growth at the cellular level, the team plans to examine how targeted muscle stimulation can be utilized to grow and repair damaged nerves, ultimately restoring mobility for individuals suffering from neurodegenerative diseases such as ALS.
“This is merely our initial step toward realizing and harnessing exercise as a form of medicine,” Raman concludes.
