Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

Cell 159, 33-45; September 25, 2014) During the preparation of Figure 1 in the article above, we inadvertently included lines separating the lanes in the western blot shown in Figure 1E. In that panel, the Vinculin control for ARC should not display separating lines, as all samples were loaded on consecutive lanes. We would like to clarify that the legends of Figures 1 and 2 should have indicated that the separating lines demarcate bands that come from nonconsecutive lanes of the same gel. Finally, in the legend of Figure 1, we did not mention that the Vinculin loading control for ARC and CamKIIa shown in Figure 1E is the same, as these proteins were detected in the same membrane. The errors do not in any way affect the results or interpretation of the figure. We apologize for any confusion that these errors may have caused.

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