We all know that lacing up and breaking a sweat is good for our mood, and that exercise can feel like a lifeline when the stresses of life threaten to engulf us. But how a pounding workout helps lift us from the encroaching gloom was a mystery -- until now.

Using mice that were stressed to the point where depression would be a predictable response, researchers at Sweden’s Karolinska Institute in Stockholm uncovered a cascade of biochemical events that begins with exercise and ends with mice that are unusually resilient in the face of stress.

Their findings, published Thursday in the journal Cell, not only illuminate the link between chronic stress and depression; they help explain how a known anti-depressive agent -- in this case exercise -- works to prevent or mitigate the debilitating mental condition. That’s more than can be said for many antidepressant medications, which clearly help many with depression, but whose mechanism of action is not all that well understood.

The findings also point the way to a novel way to ward off depression in those under stress. Antidepressant medications seem to rely largely on changing brain chemistry, and they require the use of molecules that cross the barrier that protects the brain against most bloodborne toxins. But the Swedish researchers found that exercise’s therapeutic effects begin in the muscles, and alter brain chemistry only indirectly.


Engaging in exercise is great. But finding a way to mimic exercise’s antidepressant effect could also be of “great therapeutic value” to patients who are not helped by antidepressants or who find hard exercise difficult, the authors suggested.

“It will be interesting to expand this study design to a larger cohort of human volunteers, to include also patients with depression,” the authors wrote.

Explaining the exact cascade of events that begins with endurance exercise won’t be easy. (But then, neither is hitting the gym when the world around you is going to hell in a handbasket.) Here’s what new research, gleaned both from wheel-running mice and from muscle biopsies of exercising humans, has uncovered about the mechanism by which exercise can prevent and even chase away the blues in people under stress:

Within the muscles, endurance-type exercise prompts the activation of a protein called PGC-1a1. This protein does a lot already: It promotes the growth of blood vessels, increases the efficiency with which the cells use energy, ensures that fatty acids are broken down for the body’s use, and guards against muscle atrophy.


But the authors of the latest study show that activating PGC-1a1 in the muscles also increases the production of kynurenine aminotransferases inside of muscle. And the presence of these enzymes catalyzes a chemical change in kynurenine, converting it into kynurenic acid.

In mice, and very likely in humans too, chronic stress increase levels of kynurenine in the brain -- and high levels of kynurenine appear to induce depression. But kynurenic acid can’t get into the brain, because it can’t get across the blood-brain barrier. So, when PGC-1a1 levels in muscle are high, and kynurenine gets converted into kynurenic acid, levels of kynurenine in the brain naturally drop.

The result: mental wellness in the face of disadvantage, social setbacks and general adversity.

Illuminating this process may also help explain why depression is more common among diabetics, and why there appears to be a direct link between obesity and depression. Mice who are diabetic or obese, or both, have lower levels of PGC-1a1 in their muscles. Perhaps, the authors suggested, an imbalance of PGC-1a1 and kynurenine could be the common link in many related ills.


Human trials of exercise will likely refine researchers’ understanding of this process, and help discern what kind of exercise -- say, strength-training versus endurance -- most effectively activates PGC-1a1 levels in the muscles. Such research may also make clear whether this approach is better at preventing depression or at treating it once it’s set in, and to clarify the link between PGC-1a1, stress and depression.

The link between mental and physical health is powerful, and I’m always writing about it. Follow @LATmelissahealy on Twitter.