How muscles affect the brain
During exercise, molecules are secreted that have a direct influence on the aging brain. Research into that process only got off to a good start 25 years ago with the publication of two studies by Henriette van Praag, a postdoctoral researcher at the Salk Institute for Biological Studies in California. In the papers, Van Praag described her research into the brains of adult mice that had spent a lot of time on a treadmill and mice that had not. The results showed for the first time that mammals given enough exercise made many new nerve cells, a process called neurogenesis. The observed changes were accompanied by improvements in spatial memory and learning processes.
According to Van Praag, now an assistant professor at Florida Atlantic University’s Stiles-Nicholson Brain Institute, her discovery was partly the result of chance. In a previous study, scientists had seen evidence that mice exposed to an “enriched” environment (in which they were given more and different stimuli, such as hiding places and toys) made more new nerve cells. Van Praag wanted to know what was the deciding factor in these mice. ‘Running on a treadmill was just one of the checkpoints looked at in that study,’ she laughs.
Van Praag’s work has been groundbreaking in establishing a link between neurogenesis and improved cognitive function. Not only is that very important for neurology, but it has also paved the way for exercise researchers and muscle scientists who study the interplay between exercise, muscles and the brain,” Handschin says.
In 2002, Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute and Harvard Medical School, was investigating a protein called “PGC-1α,” which regulates the body’s metabolism by turning certain genes on and off. to switch. In mice given more of this protein, Spiegelman found, the muscles became stronger, redder and better veined; it was as if the rodents had trained very hard without putting a single foot on the treadmill.
At about the same time, scientists began to realize that moving muscles secrete a variety of hormones and other molecules called myokines into the bloodstream, after which these substances could be useful in all kinds of organs. Through his research on the PGC-1α protein, Spiegelman asked himself the following question: if muscles were reminiscent of muscles that had been trained hard thanks to this protein, ‘maybe PGC-1α could induce muscles to secrete substances that are released during exercise. be created?’ He used the protein to find the molecules responsible for the positive changes in metabolism and immune response caused by exercise.
The hunt for these molecules paid off in 2012, when Spiegelman and his colleagues discovered irisin, a myokine secreted by moving muscles. The researchers were able to demonstrate that irisin is able to transform white adipose tissue into brown adipose tissue. Because brown adipose tissue burns calories (while white adipose tissue stores calories), Spiegelman suggested that irisin may hold the key to the ability to fight obesity and diabetes through exercise.
More puzzle pieces fell into place the following year, when Christiane Wrann, a postdoctoral researcher at the time working with Spiegelman, demonstrated that muscles “talked” to the brain during exercise. When muscle cells produce irisin, they enhance the production of another protein called ‘brain-derived neurotrophic factor’ (BDNF) in the hippocampus, one of the first regions of the brain to undergo changes in neurodegenerative disorders.
In the hippocampus, BDNF promotes the health and growth of synapses and nerve cells, causes these cells to reach maturity, and improves synaptic plasticity in the organ.
Last year, Wrann, now a neurologist at Massachusetts General Hospital and Harvard Medical School, tested the role of irisin in exercise and cognitive function. Her team compared mice that were genetically modified and therefore unable to produce irisin with mice in a control group that did make the molecule. The mice in the control group were better at performing spatial memory and learning tasks after a period of exercise than the mice that were unable to produce irisin, suggesting that irisin is the substance that promotes these cognitive skills.
When Wrann’s team examined the rodents’ brains more closely, they found that both groups of mice had created new nerve cells in response to exercise, but the nerve cells in the mice without irisin were abnormal: they were unable to make the usual connections. . When the researchers reintroduced the gene responsible for irisin production in the brains of the irisin-less mice, these mice were able to distinguish between two similar patterns much more easily — a skill people use, for example, when they park their car in a parking lot. have to find.
Wrann’s team also found that irisin likely plays a role in protecting against neurodegenerative disorders. The researchers bred mice that could not produce irisin and at the same time already had symptoms of Alzheimer’s. The mice with this double disability developed neurodegenerative symptoms more quickly than mice that only had Alzheimer’s. In addition, they showed signs of cognitive improvement after their irisin production was restored.
Wrann suspects that one of the ways irisin benefited these animals is that it counteracts inflammatory responses caused by a malfunction of the brain’s immune system. This system mainly consists of so-called microglia and astrocytes. These glial cells normally serve to inhibit inflammation in the brain and to clear away waste after injuries. But as mammals age, these cells can remain active after the acute danger has passed, disrupting nerve functions in the brain — first by destroying the connections between nerve cells and then by turning off the nerve cells themselves.
This activity creates the chronic inflammation in the brain associated with numerous neurodegenerative diseases, including Alzheimer’s and Parkinson’s. But lab mice treated with irisin showed less inflammation in their hippocampus, while the number of microglia and astrocytes in this region also decreased, suggesting that irisin helped bring the impaired immune defenses back under control.
Could these results also apply to humans? Perhaps, preliminary research from Wrann’s lab and other teams shows. Irisin has an identical molecular structure in mice and humans, she says, suggesting that it plays the same role in both species.
The implications of this research are promising, as it shows that people have elevated levels of irisin in their blood after fitness training. And analyzes of the brain tissue of deceased Alzheimer’s patients show that their brain tissue contains 70 percent less of the irisin precursor molecule, compared to individuals in the same age group. This suggests that irisin protects against neurodegenerative disorders.
From a clinical perspective, ‘irisin certainly shows promise,’ Handschin says, ‘particularly given the results regarding how this compound works in the brain.’ But he remains cautious: irisin has not yet been subjected to the long series of gauntlets that it will have to endure on the way to a possible application as a medicine. “It is not yet possible to say whether irisin can eventually be used in human patients.”
Depression and mood swings
Handschin is personally interested in the interactions between muscles, exercise, mood and motivation. For a study that has not yet been published, his group has investigated the effect of certain molecules released by muscle movements. Their research shows that mice that can’t make these molecules don’t feel the need to start running on a treadmill when they could — a behavior that is unusual in mice, as rodents normally run nearly six miles a day.
“There must be something going on in the muscles of these mice that somehow makes this urge – to go for a run for fun – go away,” Handschin says.
The promising potential for new treatments for mood disorders – especially major depression – is what also interests Spiegelman. He considers these conditions to be one of the least treated disorders in medicine. “Severe depression is the leading cause of suicide and is especially common in young people,” he says. He and his colleagues are currently evaluating the effect of irisin on depression in a laboratory study on mice.
The activities that take place in the brain during body movements are not limited to “talking” with muscles. The interaction between all kinds of molecules – mainly proteins – which are secreted by the liver, fat tissues and bone marrow – allows the brain to think in a more concentrated way. They also prevent the occurrence of depression and other disorders.
With scientists on the trail of promising drug candidates like irisin and others, Cortes Rodriguez of the University of Alabama believes “we are on the brink of a great era of discovery, discoveries that are finally translating into clinical practice.”
But Karina Alviña, an assistant professor of neurology at the University of Florida medical school, warns that the explosive growth of research into muscle-brain interactions is fraught with results as well as problems. The molecules involved have countless different effects on multiple systems, meaning that while their potential is enormous, deciphering all those interactions is a complex task. According to her, designing a drug without unintended side effects will still be a major challenge.
Nevertheless, Alviña looks forward to the research she and others are doing with confidence. That research shows that “the environment and the lifestyle choices we make can have a major impact on the way we age,” she says. It is therefore partly up to us to age in a healthier way and to maintain a higher quality of life until an advanced age.
“If there’s anything I can say about it, it’s that we need to stay active, even if you’re just walking for a few minutes a day. If you’re capable of that, you should definitely do it.’
This article was originally published in English on nationalgeographic.com