The first clues to the influence of muscles on the brain
The study to understand how exercise generates molecules that directly benefit brain aging began 25 years ago with the publication of two articles by Henriette van Praag, postdoc specialist in Salk Department of Biological Studies in California. These studies looked at the brains of adult mice that had spent time running on the wheel compared to mice that had not. The data showed for the first time in mammals that exercise promoted the birth of new neurons, the so-called neurogenesis, in the brains of adult mice. Added to these changes were improvements in spatial memory and learning.
Van Praag, who is now an associate professor in Stiles-Nicholson Brain Institute of Florida Atlantic University, says that the discovery was favored by a number of fortunate circumstances. In a previous study, researchers noticed signs that components in an enriched environment where mice had access to various stimuli, such as hiding places or toys, generated new neurons. So the scholar decided to find the discriminatory factor. “Running was really just one of the factors I studied,” he adds with a smile.
“Van Praag’s work helps to link race with neurogenesis and improved brain function, an important aspect not only for the neurobiological community, but also a prerequisite for researchers dealing with muscle and physical activity to study the interplay between exercise, muscles and brain, “Handschin explains.
In 2002 Bruce Spiegelman, cell biologist in Dana-Farber Cancer Institute and Harvard Medical Schoolstudied a protein called PCG1-alpha, which regulates the body’s metabolism by turning genes on and off, when he found that increasing the amount of this protein in mice made their muscles stronger, redder and full of blood vessels, as if the animal trained hard in the gym – when it had never put its paws on a treadmill before.
Around the same time, researchers began to understand that muscle movements produced hormones and other molecules, called myokines, which were released into the bloodstream and benefited distant organs. The discovery of PGC1-alpha therefore led Spiegelman to speculate: If this protein makes muscles look like those who exercise, then “it may also cause the muscles to secrete the substances produced during physical activity”. He then used the protein to find the molecules responsible for the precious changes in metabolism and immune function that exercise helps.
The research culminated in 2012 when Spiegelman and his colleagues discovered irisin, a myokin released from exercise muscles. Researchers have found that irisin converts white adipose tissue into beige adipose tissue. Because the latter burns calories, unlike the white that stores them, Spiegelman believed that irisin was the key to understanding how physical activity fights obesity and diabetes.
Other pieces of the puzzle fell into place the following year when Christiane Wrann, then a postdoc researcher working with Spiegelman, showed that muscles somehow “communicate” with the brain during physical activity. When muscle cells produce irisin, irisin increases the levels of another protein called the brain neurotrophic factor (BDNFfrom English Brain-derived neurotrophic factor) in the hippocampus, one of the first regions of the brain to undergo changes in neurodegenerative diseases. There BDNF promotes the health and growth of synapses and neurons, helps them mature and improves the plasticity of synapses.
Just last year Wrann, now neuroscientist in Massachusetts General Hospital and of Harvard Medical School, tested the role of the iris in physical activity and cognitive function. His team compared mice that were genetically engineered to be free of this hormone with control mice that still produced this molecule. After physical activity, the control mice achieved better performance in an activity based on spatial memory and learning. Since mice without irisin did not show the same improvement, it could be assumed that the molecule promoted cognitive abilities.
When examining the mice’s brains, Wrann’s team noted that both groups had produced neurons as a result of physical activity, but the new neurons in the irisin-free mice were abnormal, affecting their ability to form compounds. When the gene responsible for making irisin was added again to brains that lacked the protein, the mice had less difficulty distinguishing between two similar patterns – a useful skill for humans, such as seeing a car in a parking lot. .
Physical activity and neurodegenerative diseases
Wrann’s team also found that irisin appeared to play a role in protecting against neurodegenerative processes. The researchers bred mice that lacked irisin and showed Alzheimer’s-like symptoms. These doubly debilitated mice showed symptoms faster than mice with Alzheimer’s-like disease alone and showed cognitive progress when irisin production was re-established.
Wrann speculates that one of the contributions of irisin is the reduction of inflammation caused by malfunctions in the brain’s immune system. This system is mainly composed of microglial cells and astrocytes, which usually have the task of reducing brain infection and cleaning up waste after an injury. As mammals age, these cells can remain active even after the acute danger has ceased, disrupting the function of neurons by first destroying the connections between neurons and subsequently killing the cells themselves.
This activity causes chronic encephalitis involved in several neurodegenerative diseases, including Alzheimer’s and Parkinson’s. However, the irisin-treated laboratory mice had less inflammation in the hippocampus, and microglia cells and astrocytes were shrunk, suggesting that irisin had helped reduce the out-of-control immune response.
So are these findings valid for humans? Perhaps according to a preliminary study conducted in Wrann’s laboratory and by other teams. Irisin has an identical molecular structure in mice and humans, the scientist explains, so it is possible that it has similar functions in both species.
The results have interesting implications for the neurological benefits of physical activity, as studies show elevated levels of irisin in human blood after a workout. On the other hand, autopsy analyzes of the brain in Alzheimer’s patients reveal a 70% reduction in the precursor to irisin compared to age-matched controls, suggesting that this hormone may have a neuroprotective function.
From a therapeutic point of view, “irisin is certainly promising,” explains Handschin, “especially when looking at the data on its effects in the brain.” But the expert warns that irisin has not yet passed the long series of tests that pave the way for drug development. “It remains to be seen if it works in humans.”
Depression, anxiety and mood disorders
Handschin has a personal interest in the interplay between muscles, physical activity, mood and motivation. In an as yet unpublished study, his team examined the effects of some molecules produced by training muscles on the mice’s willingness to run on the wheel. Animals lacking these factors are able to run, but decide not to do so, an unusual behavior for a mouse, which typically runs nearly 10 km a day.
“There has to be something in the muscle that sends a signal back to the brain and somehow reduces the urge to run for fun,” Handschin explains.
The prospect of new treatments for mood disorders, especially major depression, is just as appealing to Spiegelman, who sees them as the medicine’s greatest unmet need. “Severe depression is the most common cause of suicide and is particularly prevalent among young people,” he adds. Currently, the biologist and his colleagues are evaluating the effect of irisin on anxiety-induced depression in experimental models in mice.
And during training, the brain not only “talks” to the muscles. Its interaction with molecules, especially proteins, secreted by the liver, fats and bones transforms the brain by refining thinking, protecting against depression and more.
With potential drug candidates – including irisin – on the horizon, Rodriguez of the University of Alabama believes that “we are a step away from a formidable era of breakthroughs that will finally translate into the clinical environment.”
But the explosion of research into muscle-brain interaction comes with honors and burdens, notes Karina Alviña, assistant professor of neuroscience at the University of Florida School of Medicine. Relevant molecules affect several systems in many different ways, which means that they have a potentially significant extent, but it can be difficult to navigate the many interdependencies. Designing a drug that does not have unwanted consequences will be a significant challenge.
Yet, according to Alviña, there is a glimmer of hope in the research she has conducted with other researchers: “The environment and the choice of our lifestyle can have a huge impact on how we age,” Alviña says. This means that we have the power to age healthier and maintain a better quality of life for longer.
“So if I were to sum it all up in one concept, I would say: stay active even if you just walk a few minutes a day. If possible, do it.”