• 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 T Pettersson, Duarte M S Ferreira, Anna Krook, Romain Barres, Juleen R Zierath, Sophie Erhardt, Maria Lindskog, and Jorge L Ruas.
• Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
• Cell. 2014 Sep 25;159(1):33-45.

AbstractDepression 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.Copyright © 2014 Elsevier Inc. All rights reserved.

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