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Cell. 2014 Sep 25;159(1):33-45. doi: 10.1016/j.cell.2014.07.051.

Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.

Author information

1
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
2
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
3
Department of Physiology and Pharmacology, Neuropsychoimmunology, Karolinska Institutet, 17177 Stockholm, Sweden.
4
AstraZeneca R&D, Innovative Medicines, Personalized Healthcare and Biomarkers, Translational Science Center, Science for Life Laboratory, 17165 Solna, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
5
Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
6
Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
7
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: mia.lindskog@ki.se.
8
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: jorge.ruas@ki.se.

Abstract

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.

Comment in

PMID:
25259918
DOI:
10.1016/j.cell.2014.07.051
[Indexed for MEDLINE]
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