Editors' ChoiceDepression

Outrunning Depression

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Science Translational Medicine  15 Oct 2014:
Vol. 6, Issue 258, pp. 258ec176
DOI: 10.1126/scitranslmed.aaa0484

The liver and the kidney are two organs that are known for their important role in neutralizing potentially harmful substances in our body. Their role is to filter and remove toxic substances including metabolic waste from the bloodstream. In a surprising twist, the skeletal muscle could soon be added to this list. Agudelo et al. now show that exercise training induces skeletal muscle enzymes that clear the blood of a harmful metabolite that accumulates during stress. Whereas the protective effects of exercise on stress-induced brain injury and depression are well recognized, the biochemical mechanisms responsible for the effect remain elusive. It was previously shown that endurance exercise induces production of a specific protein called PGC-1α1 that promotes skeletal muscle adaptation even in the absence of exercise. In an elegant set of experiments, the researchers discovered that mice with elevated PGC-1α1 in muscles not only displayed a healthier physique but also appeared resistant to stress-induced depression. Increased PGC-1α1 in the muscles activated a pathway that led to the conversion of kynurenine into kynurenic acid. Kynurenine is a product of tryptophan metabolism produced by the liver and immune cells during stress and inflammation. It is brain permeable and if injected into mice induces depressive-like behavior in normal mice but not in mice with elevated PGC-1α1.The exact mechanism by which kynurenine induces depression is not known, but increased kynurenine can be measured in patients with depression. Increased PGC-1α1 expression, such as that induced by exercise, efficiently clears the blood of stress-induced kynurenine by converting it into nonbrain permeable kynurenic acid. Mice that lacked PGC-1α1 in muscle displayed depressive-like behavior when unstressed and were more susceptible to kynurenine-induced depression.

These findings show that exercise induces a metabolic process in skeletal muscle that protects the brain from the adverse effects of the stress-induced metabolite kynurenine. This study suggests that skeletal muscle biochemistry could yield new potential therapeutic targets for treating depression.

L. Z. Agudelo et al., Skeletal muscle PCG-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014). [Abstract]

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