How physical exercise protects the brain from stress-induced depression
Physical exercise has many beneficial effects on human health, including the protection from stress-induced depression. However, until now the mechanisms that mediate this protective effect have been unknown. In a new study in mice, researchers at Karolinska Institutet show that exercise training induces changes in skeletal muscle that can purge the blood of a substance that accumulates during stress, and is harmful to the brain. The study is being published in the prestigious journal Cell.
“In neurobiological terms, we actually still don’t know what depression is. 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,” says Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet.
It was known that the protein PGC-1a1 (pronounced PGC-1alpha1) increases in skeletal muscle with exercise, and mediates the beneficial muscle conditioning in connection with physical activity. In this study 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).
These mice, and normal control mice, were exposed to a stressful environment, such as loud noises, flashing lights and reversed circadian rhythm at irregular intervals. After five weeks of mild stress, normal mice had developed depressive behaviour, whereas the genetically modified mice (with well-trained muscle characteristics) had no depressive symptoms.
“Our initial research hypothesis was that trained muscle would produce a substance with beneficial effects on the brain. 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,” says Jorge Ruas, principal investigator at the Department of Physiology and Pharmacology, Karolinska Institutet.
Convert a substance formed during stress
The researchers discovered that mice with higher levels of PGC-1a1 in muscle also had higher levels of enzymes called KAT. KATs convert a substance formed during stress (kynurenine) into kynurenic acid, a substance that is not able to pass from the blood to the brain. The exact function of kynurenine is not known, but high levels of kynurenine can be measured in patients with mental illness.
Well conditioned muscles make it easier for the body to purge a harmful protein associated with depression, a new study in mice suggests.
“If you consistently exercise and your muscle is conditioned and adapted to physical exercise, then you acquire the ability to express this class of enzymes that have the ability to detoxify something that accumulates during stress and that will be harmful for you,” senior study author Dr. Jorge Ruas of the Karolinska Institutet in Stockholm said in a telephone interview with Reuters Health.
The body metabolizes this substance, kynurenine, from tryptophan, a process that is activated by stress and by inflammatory factors, Dr. Ruas and his team explain in their report, published in Cell. Studies have linked high levels of kynurenine - which readily crosses the blood-brain barrier - to depression, suicide and schizophrenia.
Their new study was done in skeletal muscle-PGC-1alpha1 transgenic mice, which were genetically modified to express high levels of this protein in their muscles, mimicking the effects of aerobic muscle conditioning. The researchers subjected these mice, as well as a control group of wild-type mice, to five weeks of mild stress. The normal mice developed signs of depression, but the PGC-1alpha1 mice didn’t.
In addition to higher levels of kynurenine in their blood, the transgenic mice also had higher levels of KAT enzymes, which convert kynurenine into kynurenic acid, a more easily mebabolized form that can’t cross the blood-brain barrier.
In the current study, the researchers demonstrated that when normal mice were given kynurenine, they displayed depressive behaviour, while mice with increased levels of PGC-1a1 in muscle were not affected. In fact, these animals never show elevated kynurenine levels in their blood since the KAT enzymes in their well-trained muscles quickly convert it to kynurenic acid, resulting in a protective mechanism.
“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,” says Jorge Ruas.
350 million people affected
Depression is a common psychiatric disorder worldwide. The World Health Organization (WHO) estimates that more than 350 million people are affected.
The current study was funded by grants from the AstraZeneca-Karolinska Institutet Integrated Translational Research Centre, the Novo Nordisk Foundation, the Petrus and Augusta Hedlund Foundation, Stockholm County Council, Karolinska Institutet’s Strategic Research Programme in Diabetes, the Swedish Brain Foundation, the Swedish Diabetes Association, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Åhlén Foundation and the Åke Wiberg Foundation, among others.
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Publication
Skeletal Muscle PGC-1a1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression
Leandro Z. Agudelo, Teresa Femenía, Funda Orhan, Margareta Porsmyr-Palmertz, Michel Goiny, Vicente Martinez-Redondo, Jorge C. Correia, Manizheh Izadi, Maria Bhat, Ina Schuppe-Koistinen, Amanda Pettersson, Duarte M. S. Ferreira, Anna Krook, Romain Barres, Juleen R. Zierath, Sophie Erhardt, Maria Lindskog, and Jorge L. Ruas
Cell, online 25 September 2014
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Karolinska Institutet
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