Exercise protects against depression - but how?

A new study, published in the journal Cell, investigates the mechanisms behind the protection from stress-induced depression offered by physical exercise.

Exercise has well-known benefits against symptoms of depression.

Exercise has well-known benefits against symptoms of depression.

Last year, an updated systematic review by UK researchers analyzed 35 randomized controlled trials on the subject involving a total of 1,356 participants diagnosed with depression.

The systematic review found that exercising was as beneficial for people with depression as psychological therapy or taking antidepressants. However, the researchers cautioned that higher quality studies are needed to confirm the results.

Scientists know that during exercise, there is an increase in skeletal muscle of a protein called PGC-1a1. The researchers behind the new study - from the Karolinska Institutet in Sweden - wanted to see whether this protein increase might be implicated in the protective benefits of exercise.

Genetically modified mice with high levels of PGC-1a1 in skeletal muscle (that showed many characteristics of well-trained muscles) were exposed - along with normal mice - to a stressful environment in the lab. This involved being exposed to loud noises, flashing nights and having their circadian rhythm reversed at irregular intervals.

After 5 weeks of being exposed to mild stress, the normal mice developed symptoms of depression, whereas the genetically modified mice displayed no depressive behavior.

The initial research hypothesis was that trained muscle would produce a substance with beneficial effects on the brain - Department of Physiology and Pharmacology, Karolinska Institutet.

"We actually found the opposite: well-trained muscle produces an enzyme that purges the body of harmful substances. So in this context the muscle's function is reminiscent of that of the kidney or the liver."

Investigating the genetically modified mice further, the researchers made the discovery that - as well as the elevated levels of PGC-1a1 - the mice also had higher levels of KAT enzymes. These enzymes convert kynurenine - a substance formed during stress - into kynurenic acid. 

The exact function of this acid is not known, but patients with mental illness are known to have high levels of it.

Kynurenine conversion process 'may be protective mechanism'

When normal mice were given kynurenine as part of the study, the researchers found that they exhibited symptoms of depression. However, when the elevated PGC-1a1 mice were given kynurenine, their behavior seemed unaffected.

The researchers also noticed that even when the PGC-1a1 mice were administered kynurenine, their blood did not show raised levels of kynurenine. This is because the KAT enzymes in the trained muscles of the PGC-1a1 mice were able to quickly convert it to kynurenic acid. The researchers think that this quick conversion process therefore, is a protective mechanism.

In neurobiological terms, the researchers actually still don't know what depression is. Their study represents another piece in the puzzle, since we provide an explanation for the protective biochemical changes induced by physical exercise that prevent the brain from being damaged during stress.

It's possible that this work opens up a new pharmacological principle in the treatment of depression, where attempts could be made to influence skeletal muscle function instead of targeting the brain directly. Skeletal muscle appears to have a detoxification effect that, when activated, can protect the brain from insults and related mental illness.