Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Cell |
Volume | 159 |
Issue number | 1 |
Pages (from-to) | 33-45 |
Number of pages | 13 |
ISSN | 0092-8674 |
DOIs | |
Publication status | Published - 25 Sep 2014 |
- Animals, Blood-Brain Barrier, Depression, Gene Expression Profiling, Humans, Kynurenic Acid, Kynurenine, Mice, Muscle Fibers, Skeletal, Muscle, Skeletal, PPAR alpha, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Physical Conditioning, Animal, Physical Conditioning, Human, Stress, Psychological, Transaminases, Transcription Factors, Journal Article, Research Support, Non-U.S. Gov't
Research areas
ID: 172479176