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How exercise protects the brain from stress-induced depression

That physical exercise guards against stress-induced depression is well documented – and indeed a 2013 review in which UK researchers analysed 35 randomized controlled trials involving 1356 participants diagnosed with depression confirmed that exercising was as beneficial for people with depression as psychological therapy or taking antidepressants.

However, the mechanisms behind this have been unknown – until now. In positive news for the estimated 350 million people worldwide who suffer depression (according to World Health Organization estimates), new research from Sweden’s Karolinska Institutet, to be published in the journal Cell, shows that exercise training induces changes in skeletal muscle that can purge the blood of a substance harmful to the brain that accumulates during stress.

“In neurobiological terms, we actually still don’t know what depression is,” remarks Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet. “Our 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 was known that the protein PGC-1a1 (pronounced PGC-1alpha1) increases in skeletal muscle with exercise, and also mediates the beneficial muscle conditioning in connection with physical activity.

The researchers used a genetically modified mouse with high levels of PGC-1a1 in skeletal muscle that shows many characteristics of well-trained muscles, even without exercising. This group of mice, and a control group of normal mice, were exposed to a stressful environment that included at irregular intervals loud noises, flashing lights and reversed circadian rhythm. After five weeks, the normal mice had developed depressive behaviour, whereas the genetically modified mice with well-trained muscle characteristics were free of depressive symptoms.

The research team’s initial hypothesis was that trained muscle would produce a substance with beneficial effects on the brain. But they 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,” says Jorge Ruas, principal investigator at the Department of Physiology and Pharmacology, Karolinska Institutet.

The mice with higher muscle levels of PGC-1a1 also had higher levels of enzymes called KAT. KATs convert kynurenine, a substance formed during stress, into kynurenic acid, a substance that lacks the ability to cross the bload-brain barrier. While the precise function of kynurenine is unknown, high levels can be measured in patients suffering mental illness.

The researchers demonstrated in this study that normal mice given kynurenine displayed depressive behaviour, while mice with increased levels of PGC-1a1 in muscle were not affected. Moreover, the latter group at no stage exhibited elevated kynurenine levels in their blood as the KAT enzymes in their trained muscles rapidly converted it to kynurenic acid, resulting in a protective mechanism.

Ruas predicts this work has the potential to open up a new pharmacological principle in the treatment of depression, targeting the skeletal muscle function targeted rather than the brain. “Skeletal muscle appears to have a detoxification effect that, when activated, can protect the brain from insults and related mental illness,” he adds.

Written for the Australian Traditional-Medicine Society (ATMS) by Rosemary Ann Ogilvie from materials released by Karolinska Institutet.

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