Endurance brain cells can determine how long you can run

Scientists have identified neurons in mice that help build endurance after running. They suspect that similar cells exist in humans that could be targeted by drugs or other therapies to enhance the effects of exercise.

We have known for decades that physical activity changes the brain. Still, scientists have widely believed that these effects are different from those that occur elsewhere in the body, such as the muscles that get stronger, he says Nicholas Betley at the University of Pennsylvania. The latest findings suggest otherwise — changes in the brain “are what coordinates all the other things,” he says.

To better understand how exercise affects the brain, Betley and his colleagues monitored neuronal activity in mice before, during and after treadmill exercise. They targeted cells in the ventromedial hypothalamus, as previous research had shown disturbed development in this area of ​​the brain prevents the improvement of the condition of the rodents. The same is likely true in humans, as the region’s structure and function tend to be consistent across mammals, Betley says.

The team found that after the mice ran, activity increased in a group of neurons with a receptor called SF1, which plays a role in brain development and metabolism. What’s more, the proportion of these cells activated by exercise increased with each passing day of running. By the eighth day, running had activated about 53 percent of the neurons, compared with less than 32 percent on the first day. “So just as you build muscles when you exercise, your brain activity also increases,” says Betley.

Next, the researchers used optogenetics—a technique that activates or inhibits neuronal activity with light—to turn off these neurons in a separate group of mice. Animals trained on a treadmill five days a week for three weeks. After each session, neurons were inhibited for one hour. At the end of each week, the mice completed an endurance test, running until exhaustion.

Over the course of the experiment, the mice increased the distance they ran in these tests by an average of about 400 meters, but that was about half the improvement seen in another group of mice whose neurons remained intact.

It’s not clear what the role of these neurons is, but it may be related to fuel utilization, the team member says Morgan Kindelalso at the University of Pennsylvania. During endurance activities, the body stores fat because carbohydrate stores are depleted more quickly. But inhibiting these neurons in the mice caused them to “start using carbohydrates much earlier during running,” Kindel says. “Then they kind of run out of fuel. The team found that inhibiting these neurons prevents the release of a protein called PGC-1 alpha in muscles, which helps cells use fuel more efficiently. These neurons also release a substance that raises blood sugar and replenishes energy stores, helping muscle recovery.

Optogenetics requires invasive brain surgery, so it is not feasible in humans. But it may be possible to develop other interventions that could act on these neurons, Betley says. “I really think that if we could find a way—a salt, a supplement—to activate those neurons, you could increase endurance,” says Betley.

When the researchers repeated the experiment and increased rather than inhibited the activity in these neurons, they found just that: the mice developed Herculean endurance, running more than twice the distance of the control mice.

A similar intervention could particularly benefit people who have difficulty exercising, such as older adults or those who have had a stroke, Betley says.

But there are many obstacles in the way. First, we don’t know for sure whether these findings translate to humans. There’s also the issue of potential side effects, he says Thomas Burris at the University of Florida. These neurons seem to regulate energy intake in the muscles, so overstimulating them could cause a dangerous drop in blood sugar, he says.

Even if we can safely activate these neurons in humans, it won’t be a silver bullet for good health, Betley says. “When you exercise, all kinds of great things happen—you’re less depressed, less anxious. There’s better cognitive function, better cardiovascular system, better muscle,” he says. “I don’t think it’s activating. [these] neurons necessarily become the bottleneck through which all the good stuff happens.”

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