Research explores how exercise keeps brain healthy

| Monday, Oct. 14, 2013, 12:01 a.m.

While our muscles pump iron, our cells pump out something else: molecules that help maintain a healthy brain.

But scientists have struggled to account for the well-known mental benefits of exercise: from counteracting depression and aging to fighting Alzheimer's and Parkinson's disease.

A research team may have finally found a molecular link between a workout and a healthy brain.

Much exercise research focuses on the parts of our body that do the heavy lifting. Muscle cells ramp up production of a protein called FNDC5 during a workout.

A fragment of this protein, known as irisin, gets lopped off and released into the bloodstream, where it drives the formation of brown fat cells, thought to protect against diseases such as diabetes and obesity.

While studying the effects of FNDC5 in muscles, cellular biologist Bruce Spiegelman of Harvard Medical School in Boston happened upon startling results: Mice that did not produce a so-called co-activator of FNDC5 production, known as PGC-1a, were hyperactive and had tiny holes in certain parts of their brains. Other studies showed that FNDC5 and PGC-1a are present in the brain, not just the muscles, and that both might play a role in the development of neurons.

Spiegelman and his colleagues suspected that FNDC5 (and the irisin made from it) was responsible for exercise-induced benefits to the brain-in particular, increased levels of a crucial protein called brain-derived neurotrophic factor, which is essential for maintaining healthy neurons and creating new ones.

These functions are crucial to staving off neurological diseases, including Alzheimer's and Parkinson's. And the link between exercise and BDNF is widely accepted.

“The phenomenon has been established over the course of, easily, the last decade,” said neuroscientist Barbara Hempstead of Weill Cornell Medical College in New York, who was not involved in the new work. “It's just, we didn't understand the mechanism.”

To sort out that mechanism, Spiegelman and his colleagues performed a series of experiments in living mice and cultured mouse brain cells.

First, they put mice on a 30-day endurance training regimen. They didn't have to coerce their subjects, because running is part of a mouse's natural foraging behavior. “It's harder to get them to lift weights,” Spiegelman notes. The mice with access to a running wheel ran the equivalent of a 5K every night.

Aside from physical differences between wheel-trained mice and sedentary ones — “they just look a little bit more like a couch potato,” said co-author Christiane Wrann of Harvard Medical School of the latter's plumper figures, the groups showed neurological differences. The runners had more FNDC5 in their hippocampus, an area of the brain responsible for learning and memory.

So how is the brain getting the signal to make BDNF?

Some have theorized that neural activity during exercise accounts for changes in the brain. But it's possible that factors outside the brain, like those proteins secreted from muscle cells, are the driving force.

To test whether irisin made elsewhere in the body can still drive BDNF production in the brain, the group injected a virus into the mouse's bloodstream that causes the liver to produce and secrete elevated levels of irisin.

They saw the same effect as in exercise: increased BDNF levels in the hippocampus. This suggests that irisin could be capable of passing the blood-brain barrier, or that it regulates some other (unknown) molecule that crosses into the brain, Spiegelman says.

Hempstead calls the findings “very exciting,” and believes this research finally begins to explain how exercise relates to BDNF and other so-called neurotrophins that keep the brain healthy. “I think it answers the question that most of us have posed in our own heads for many years.”

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