Exercise is known to help maintain muscle mass and strength longer, especially in the elderly, but new research suggests that starting regular exercise earlier in life is the key to optimal muscle aging.

While these earlier studies have shown that physical activity slows age-related muscle decline, exactly how this happens — and the reasons for muscle loss with age — isn’t totally clear.

“I think everybody can relate to the fact that people who have exercised all their lives, to some degree, they do better when they get old, their muscles are bigger and they have better function,” said Abigail Mackey, professor at the University of Copenhagen and Institute of Sports Medicine Copenhagen. “And we actually still don’t know why, it’s quite puzzling.”

One clue comes from a study of human cadavers, which showed older people had fewer motor neurons than younger people. These specialized nerve cells relay messages from the brain to our muscle fibres. Once a motor neuron is lost, due to injury or age, the set of muscle fibres connected to that neuron no longer receive messages and begin to atrophy.

“Unlike many other cell types, [motor neurons] cannot renew,” explained Casper Soendenbroe, a post-doctoral researcher working with Mackey. Therefore, they hypothesize that the loss of motor neurons over time could result in age-related muscle loss.

It comes down to motor neurons…

Operating under this assumption, Soendenbroe and Mackey set out to investigate how lifelong recreational exercise, meaning the sorts of light sports or exercise that many of us do for fun and to stay fit, affects motor neuron loss.  

“In these lifelong exercisers, is there something in the muscle fibres that’s signalling to the motor neurons that would preserve motor neuron numbers?” Mackey wondered.

It is not possible to do these types of experiments with actual people, so the pair turned to cell cultures instead. They recruited individuals of the same age who regularly exercised throughout their life or who had a sedentary lifestyle. Each group had several participants from whom samples of two cell types, muscle stem cells and fibroblasts, were taken.

Motor neurons were then grown alongside the cells so they could assess the difference in how the cells from exercisers or sedentary individuals stimulated motor neuron growth and survival.

In this setup, muscle stem cells were used because in the lab they fuse together and form structures resembling the precursors of muscle fibres. The motor neurons grow into these as they would muscles, mimicking what happens in the body. Any positive effects on motor neurons would be attributable to differences in stem cells produced by exercise.

The fibroblasts, which have the bad reputation of being involved in scarring and other injury related problems, were used as a control. “The idea was, they’re not going to do anything good to the motor neurons,” explained Soendenbroe, “If anything, they might even be affecting them negatively.”

As expected, cells from exercisers protected motor neurons better than those from sedentary individuals. However, they were surprised to see similar positive effects for the motor neurons grown with fibroblasts from the exercise group.

According to Soendenbroe, “[fibroblasts] were able to stimulate the motor neurons positively to the same extent, and sometimes even better, than the muscle stem cells.”

Digging deeper into this unexpected result, they looked at which genes were being turned on and off in the two cell types and saw a completely different pattern.

“[Fibroblasts] stimulated different processes in the motor neurons than the muscle stem cells,” explained Mackey. In another twist, the team tested the medium from cell cultures containing only muscle stem cells or fibroblasts. This medium contains all the things secreted by the cells and when it was provided to the motor neurons, the fibroblast medium outperformed the stem cells.

This paints a complicated picture of how the muscle stem cells and fibroblasts are working to protect motor neurons. “Probably fibroblasts and muscle stem cells are working together to support motor neurons,” Mackey said. The two cell types appear to be providing different types of support to the neurons in direct and indirect ways.

Start exercising early!

For Mackey, this study shows that there are “no bad guys” when it comes to cells in the muscles and there are likely many more players yet to be discovered.

For both Mackey and Soendenbroe, the take home message for the public is to start exercising early in life so the cells are conditioned to protect motor neurons before they are lost. There was a clear improvement in survival of the motor neurons from the cells of lifelong exercisers. “It didn’t matter which cell type it was, as long as it came from the lifelong exercise,” said Soendenbroe.

“Everyone says it’s never too late to take up exercise, and we shouldn’t change that message, because there’s so many other health benefits regardless,” explained Mackey. “But if you’re thinking specifically about number of muscle fibres, there probably is a point where it’s too late,” she said. “So, exercise could preserve the number of muscle fibres if we do it throughout our life and don’t wait until we get old,”

It remains to be seen exactly what changes the cells of exercisers go through and how this protects motor neuron loss but as Mackey said, “you need to maintain a decent level of physical activity throughout your life to preserve motor neurons.” 

Reference: Casper Soendenbroe, Abigail L. Mackey et al. Muscle fibroblasts and stem cells stimulate motor neurons in an age and exercise-dependent manner, Aging Cell (2024). DOI: 10.1111/acel.14413

Feature image credit: Gabin Vallet on Unsplash