title: Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.
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.
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Leandro Z
authors.initials: LZ
authors.lastname: Agudelo
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Teresa
authors.initials: T
authors.lastname: Femenía
authors.affiliation: Department of Physiology and Pharmacology, Neuropsychoimmunology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Funda
authors.initials: F
authors.lastname: Orhan
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Porsmyr-Palmertz
authors.affiliation: Department of Physiology and Pharmacology, Neuropsychoimmunology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Michel
authors.initials: M
authors.lastname: Goiny
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Vicente
authors.initials: V
authors.lastname: Martinez-Redondo
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Jorge C
authors.initials: JC
authors.lastname: Correia
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Manizheh
authors.initials: M
authors.lastname: Izadi
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Bhat
authors.affiliation: 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.
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Pettersson
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Duarte M S
authors.initials: DMS
authors.lastname: Ferreira
authors.affiliation: Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.affiliation: Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Romain
authors.initials: R
authors.lastname: Barres
authors.affiliation: 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.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: Department of Physiology and Pharmacology, Neuropsychoimmunology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: mia.lindskog@ki.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindskog
authors.affiliation: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: jorge.ruas@ki.se.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D003863:Depression / Q000378:metabolism / Q000517:prevention & control*; D020869:Gene Expression Profiling; D006801:Humans; D007736:Kynurenic Acid; D007737:Kynurenine / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D064797:Physical Conditioning, Human; D013315:Stress, Psychological / Q000150:complications*; D000637:Transaminases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047493:PPAR alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D007737:Kynurenine; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid