Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle

Abstract Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, main...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Chongye Fang, Shuhei Hayashi, Xiaocui Du, Xianbin Cai, Bin Deng, Hongmei Zheng, Satoshi Ishido, Hiroko Tsutsui, Jun Sheng
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2021
Materias:
R
Q
Acceso en línea:https://doaj.org/article/5b4f3709787b4fb0ba7fd5b3e7edd370
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:5b4f3709787b4fb0ba7fd5b3e7edd370
record_format dspace
spelling oai:doaj.org-article:5b4f3709787b4fb0ba7fd5b3e7edd3702021-12-02T14:23:04ZCaffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle10.1038/s41598-021-86659-42045-2322https://doaj.org/article/5b4f3709787b4fb0ba7fd5b3e7edd3702021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86659-4https://doaj.org/toc/2045-2322Abstract Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.Chongye FangShuhei HayashiXiaocui DuXianbin CaiBin DengHongmei ZhengSatoshi IshidoHiroko TsutsuiJun ShengNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Chongye Fang
Shuhei Hayashi
Xiaocui Du
Xianbin Cai
Bin Deng
Hongmei Zheng
Satoshi Ishido
Hiroko Tsutsui
Jun Sheng
Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
description Abstract Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.
format article
author Chongye Fang
Shuhei Hayashi
Xiaocui Du
Xianbin Cai
Bin Deng
Hongmei Zheng
Satoshi Ishido
Hiroko Tsutsui
Jun Sheng
author_facet Chongye Fang
Shuhei Hayashi
Xiaocui Du
Xianbin Cai
Bin Deng
Hongmei Zheng
Satoshi Ishido
Hiroko Tsutsui
Jun Sheng
author_sort Chongye Fang
title Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_short Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_full Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_fullStr Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_full_unstemmed Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_sort caffeine protects against stress-induced murine depression through activation of pparγc1α-mediated restoration of the kynurenine pathway in the skeletal muscle
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/5b4f3709787b4fb0ba7fd5b3e7edd370
work_keys_str_mv AT chongyefang caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT shuheihayashi caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT xiaocuidu caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT xianbincai caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT bindeng caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT hongmeizheng caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT satoshiishido caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT hirokotsutsui caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
AT junsheng caffeineprotectsagainststressinducedmurinedepressionthroughactivationofppargc1amediatedrestorationofthekynureninepathwayintheskeletalmuscle
_version_ 1718391487170871296