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

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; Jorge L Ruas

doi:10.1016/j.cell.2014.07.051

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

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, Jorge L Ruas

333 Citations (Scopus)

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.

Original language	English
Journal	Cell
Volume	159
Issue number	1
Pages (from-to)	33-45
Number of pages	13
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2014.07.051
Publication status	Published - 25 Sept 2014

Keywords

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

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http://www.cell.com/article/S0092867414010496/pdf

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Agudelo, L. Z., Femenía, T., Orhan, F., Porsmyr-Palmertz, M., Goiny, M., Martinez-Redondo, V., Correia, J. C., Izadi, M., Bhat, M., Schuppe-Koistinen, I., Pettersson, A. T., Ferreira, D. M. S., Krook, A., Barres, R., Zierath, J. R., Erhardt, S., Lindskog, M., & Ruas, J. L. (2014). Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell, 159(1), 33-45. https://doi.org/10.1016/j.cell.2014.07.051

Agudelo, LZ, Femenía, T, Orhan, F, Porsmyr-Palmertz, M, Goiny, M, Martinez-Redondo, V, Correia, JC, Izadi, M, Bhat, M, Schuppe-Koistinen, I, Pettersson, AT, Ferreira, DMS, Krook, A, Barres, R , Zierath, JR, Erhardt, S, Lindskog, M & Ruas, JL 2014, 'Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression', Cell, vol. 159, no. 1, pp. 33-45. https://doi.org/10.1016/j.cell.2014.07.051

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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.",

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AU - Goiny, Michel

AU - Martinez-Redondo, Vicente

AU - Correia, Jorge C

AU - Izadi, Manizheh

AU - Bhat, Maria

AU - Schuppe-Koistinen, Ina

AU - Pettersson, Amanda T

AU - Ferreira, Duarte M S

AU - Krook, Anna

AU - Barres, Romain

AU - Zierath, Juleen R

AU - Erhardt, Sophie

AU - Lindskog, Maria

AU - Ruas, Jorge L

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N2 - 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.

AB - 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.

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KW - Blood-Brain Barrier

KW - Depression

KW - Gene Expression Profiling

KW - Humans

KW - Kynurenic Acid

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KW - Muscle Fibers, Skeletal

KW - Muscle, Skeletal

KW - PPAR alpha

KW - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

KW - Physical Conditioning, Animal

KW - Physical Conditioning, Human

KW - Stress, Psychological

KW - Transaminases

KW - Transcription Factors

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KW - Research Support, Non-U.S. Gov't

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DO - 10.1016/j.cell.2014.07.051

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SP - 33

EP - 45

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Keywords

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