Mighty muscles may stave off depression

A powerful body can protect the brain, a new study suggests. Toned muscles filter a toxin from the brain and keep depression at bay, researchers report in the Sept. 25 Cell.

By discovering a previously unknown link between muscles and brain in mice, the results provide compelling evidence for the healing power of exercise, says psychiatrist Andrew Miller of Emory University in Atlanta. “This paper really emphasizes ‘strong body, strong mind.’” The finding also hints at new ways to treat brain disorders, he says.

Researchers have known that in response to a good workout, muscles produce a compound called PGC-1 alpha 1, which is a general do-gooder around the body. The compound prompts the body to make more blood vessels and mitochondria, for instance. The new study, which includes tests involving a small number of people, shows that PGC-1 alpha 1’s rejuvenating effects extend to the brain.

In the study, mice were exposed to five weeks of unpredictable stressors, such as food deprivation, strobe lights and loud noises. At the end of their ordeal, mice showed signs of stress-induced depression, such as not drinking as much sweet water and giving up in a tank of water instead of struggling to swim. These mice’s brains also showed signs of depression: Key genes changed their behavior in response to the stress. 

But mice genetically tweaked to produce more PGC-1 alpha 1 in their skeletal muscles seemed immune to chronic stress and showed fewer of these depressive signs, says study coauthor Maria Lindskog of the Karolinska Institutet in Stockholm. “Nothing happened,” she says. “The brain was completely protected.”

When produced in response to exercise, PGC-1 alpha 1 kicks off a chain of chemical events in muscles that culminates in neutralizing a stress-induced toxin called kynurenine. An injection of kynurenine, which travels easily between the body and brain, caused mice to show signs of depression, even when the animals weren’t exposed to stressors. That result “suggests kynurenine may be a much more malignant molecule than we had previously appreciated,” Miller says.

But PGC-1 alpha 1 in the muscle leads to conversion of kynurenine into a form that can’t pass into the brain.  The results show how muscle can have a profound effect on other organs, Lindskog says. “It’s like a detoxifying organ, almost.”

Mice that ran on an exercise wheel, covering more than 4 kilometers a night for 8 weeks, also experienced benefits, the team found. And there are hints that people could achieve the same protection via working out. After three weeks of exercise, volunteers’ muscles produced more kynurenine-neutralizing molecules, biopsies from thigh muscles showed.

To get the benefits, people would need to routinely challenge their muscles, which means regularly upping their exercise regimens, Lindskog says. An easy daily walk probably wouldn’t be rigorous enough to boost PGC-1 alpha 1 production.

A subset of people with depression might benefit strongly from exercise therapy, or from drugs developed to target kynurenine or the molecules that interact with it, Miller says. And the benefits probably wouldn’t stop at depression. People with cancer, autoimmune disorders or other diseases that involve inflammation might benefit from stronger muscles, he says. “All of those are going to be associated with high levels of kynurenine,” he says. “And we now know that we can begin to possibly clear out the system by encouraging patients to exercise.”