Caffeine protects against stress-induced murine depression through activation of PPAR\u03b3C1\u03b1-mediated restoration of the kynurenine pathway in the skeletal muscle

Chongye Fang,Bin Deng,Xianbin Cai,Xiaocui Du,Jun Sheng,Shuhei Hayashi,Hiroko Tsutsui,Hongmei Zheng,Satoshi Ishido

doi:10.1038/s41598-021-86659-4

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.

Highlights

Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway
MG132, a proteasome inhibitor, suppressed the caffeine induction of PGC-1α (Fig. 6d). These results suggest that caffeine upregulates PGC-1α levels by inhibiting proteasomal degradation, which evokes kynurenine aminotransferase-1 (KAT1) in the skeletal muscle, eventually leading to the reduction in circular KYN and presumably brain KYN through the conversion of blood brain barrier (BBB)-permeable KYN to BBB-impermeable kynurenic acid (KYNA) (Fig. 7)
Caffeine intake promoted the conversion of KYN to KYNA (Figs. 2a,b, 7), presumably by inducing KAT1 expression in the skeletal muscle (Figs. 3, 7), and activated myotubes to express robust PGC-1α (Figs. 6, 7)

Summary

Introduction

Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. 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. Caffeine and other selective adenosine receptor antagonists have been proposed as therapeutic agents for the treatment of motivational dysfunction in depression[23,25] It remains to be elucidated whether and how caffeine modulates the kynurenine pathway to protect against depression. Mice administered with caffeine in drinking water exhibited selective induction of Il6 in their skeletal muscle[26] This feature, common to exercise training and caffeine intake, prompted us to investigate whether caffeine prevents stress-induced depression by activating the PGC-1α-KAT axis in the skeletal muscle of mice

Methods

Results

Conclusion