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Exercise as Brain Therapy: Muscle Activity That Promotes Neuron Health

There's no question that physical activity contributes significantly to health, fortifying muscles and improving the function of bones, blood, vessels, and the immune system.

Muscle Activity and Neuron Growth

MIT engineers have discovered that exercise benefits extend to individual neurons, observing that muscle contractions release a complex array of biochemical signals known as myokines.

Neurons exposed to these muscle-generated signals grew four times farther than those without myokine exposure, indicating a substantial biochemical effect of exercise on nerve growth at the cellular level.

The researchers were intrigued to find that neurons respond not only to the biochemical signals generated by exercise but also to its physical effects. Repeatedly pulling neurons, in a manner mimicking muscle expansion and contraction, led to growth on par with myokine exposure.

Muscle-Generated Signals and Their Impact

Previous studies hinted at a biochemical connection between muscle activity and nerve growth, but this research is the first to demonstrate that physical effects play an equally significant role, the researchers report. Published in Advanced Healthcare Materials, the findings illuminate how muscles and nerves interact during exercise and may aid in developing exercise-based therapies to repair damaged or deteriorating nerves.

Potential for Exercise-Based Therapies

"Understanding this muscle-nerve crosstalk opens new avenues for treating conditions such as nerve injuries, where nerve-muscle communication is disrupted," say Ritu, Raman, the Eugene Bell Career Development Assistant Professor of Mechanical Engineering at MIT.

Muscle Stimulation as a Pathway for Nerve Regeneration

"Muscle Stimulation could serve as a pathway to encourage nerve regeneration, helping to regain mobility for those impacted by traumatic injuries or neurodegenerative conditions."

Study Team and Contributions

The new study is led by senior author Ritu Raman, with contributions from Angel Bu, Ferdows Afghah, Nicolas Castro, Maheera Bawa, Sonika Kohli, Karina Shah, and Brandon Rios from MIT's Department of Mechanical Engineering, and Vincent Butty from MIT's Koch Institute for Integrative Cancer Research.

Muscle Communication: Insights from Previous Research

In 2023, Raman and her team demonstrated that mobility could be restored in mice with traumatic muscle injuries by implanting muscle tissue at the injury site and stimulating it repeatedly with light to simulate exercise.

Over time, the researchers observed that the exercised graft enabled the mice to recover motor function, achieving activity levels similar to those of healthy mice.

The researchers discovered that regular exercise induced the grafted muscle to produce biochemical signals, which are recognized for promoting nerve and blood vessel development.

Muscle-Nerve Communication: New Perspectives

"It's intriguing because we typically assume nerves control muscles, but we rarely consider the possibility of muscles communicating back to nerves," says Raman.

"We began to consider that stimulating the muscle might be promoting nerve growth. However, responses suggested that while this could be true, there are hundreds of other cell types in the body, making it difficult to prove whether nerve growth is directly due to the muscle or if other factors, like the immune system, are involved," says Raman.

Investigating the Impact of Exercise on Nerve Growth

In their latest research, the team aimed to investigate whether exercise has a direct impact on nerve growth by focusing exclusively on muscle and nerve tissues. They cultured mouse muscle cells into elongated fibers, which then fused to create a small sheet of mature muscle tissue roughly the size of a quarter.

Engineering Muscle Cells for Exercise Simulation

The researchers genetically modified the muscle to respond to light by contracting. With this alteration, they were able to flash light repeatedly, causing the muscle to contract in a way that replicated the effects of exercise.

Video

Scientists at MIT found that motor neurons showed a marked increase in growth over five days when subjected to exercise-related biochemical and mechanical signals. The green ball illustrates the clusters of neurons growing outward as axons. Credit: Angel Bu.

Raman developed a novel gel mat specifically designed to grow and stimulate muscle tissue. Its specialized properties ensure the muscle tissue remains anchored, even as it undergoes repeated stimulation for exercise.

Collection of Myokine Solution

The team proceeded to collect samples of the surrounding solution in which the muscle tissue was exercised, hypothesizing that the solution would contain myokines, growth factors, RNA, and various other proteins.

Raman characterizes myokines as a biochemical blend of substances secreted by muscles, with certain components possibly benefiting nerve growth, while others may have no connection to nerves. "While muscles are always releasing myokines, exercise amplifies  this secretion," she says.

Exercise-Induced Myokines and Their Impact on Neurons

The team moved the myokine solution to a separate dish containing motor neurons, which are responsible for controlling muscles involved in voluntary movement, specifically those located in the spinal cord. The neurons were cultured from stem cells derived from mice.

Enhanced Neuron Growth Due to Myokines

Similar to the muscle tissue, the neurons were cultured on a comparable gel mat. Upon exposure to the myokine mixture, the researchers noted that the neurons grew four times faster than those not treated with the biochemical solution.

Raman observes that the neurons grow significantly faster and farther, with the impact being almost immediate.

Genetic Analysis of Neuronal Changes

To examine the impact of exercise-induced myokines on neuronal changes, the team conducted a genetic analysis by extracting RNA from the neurons to assess any alterations in the expression of specific neuronal genes.

Raman explains that the genes up-regulated in the exercise-stimulated neurons were associated not only with growth, but also with neuronal maturation, communication with muscles and other nerves, and axon development. "Exercise appears to affect both growth and the functionality of neurons," she notes.

Physical Effects of Exercise on Neurons

The results point to the fact that the biochemical responses to exercise can enhance neuron growth. The next logical question for the team was: Could the physical impacts of exercise also provide such benefits?

Mechanical Stimulation of Neurons

Raman notes that because neurons are physically attached to muscles, they naturally stretch and move with them. "We were curious to see if, even without the biochemical signals from the muscle, replicating the mechanical effects of exercise by stretching the neurons could lead to growth," she explains.

To explore this question, the researchers cultured a separate batch of motor neurons on a gel mat integrated with tiny magnets. By using an external magnet, they were able to induce movement, causing both the mat and the neurons to oscillate.

By applying this mechanical stimulation for 30 minutes daily, the researchers effectively 'exercised' the neurons.

Surprising Results: Physical Exercise Promotes Neuron Growth

They were surprised to find that this physical exercise promoted neuron growth as significantly as the myokine-induced stimulation, with the neurons growing far more than those that received no exercise.

"This is a promising result, as it suggests that both the biochemical and physical effects of exercise play equally significant roles," says Raman.

Future Research Directions

Now that the group has established that muscle exercise can promote cellular nerve growth, their upcoming research will focus on how targeted stimulation of muscles may help heal damaged nerves and restore mobility in individuals living with neurodegenerative diseases such ALS.

According to Raman, this marks just the beginning of their journey toward understanding and utilizing exercise as a therapeutic tool.

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