Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
Chongye Fang, Shuhei Hayashi, Xiaocui Du, Xianbin Cai, Bin Deng, Hongmei Zheng et al. · 2021 · 12 citationsRead the paper
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.
What the full text shows
Shown in the lab- Caffeine supplementation reduced immobility time in forced swimming and tail suspension tests in CMS-exposed mice to levels comparable to controls. (CMS-exposed male C57BL/6J mice; 0.5 mg/mL caffeine in drinking water for 6 weeks)
- Caffeine restored plasma levels of pro-neurotoxic kynurenine (KYN) and neuroprotective kynurenic acid (KYNA) in CMS-exposed mice. (CMS-exposed male C57BL/6J mice; 0.5 mg/mL caffeine in drinking water for 6 weeks)
- Caffeine treatment restored KAT1 protein and mRNA levels in the skeletal muscle of CMS-exposed mice. (CMS-exposed male C57BL/6J mice; 0.5 mg/mL caffeine in drinking water for 6 weeks)
- Caffeine increased PGC-1α protein levels in murine myotubes by inhibiting proteasomal degradation. — Peak levels at 15-30 min post-incubation (C2C12 murine myotubes)
- Caffeine induced KAT1 expression in a dose- and duration-dependent manner in murine myotubes. (C2C12 murine myotubes; 400 μg/mL caffeine)
- Caffeine did not rescue the reduction in weight gain caused by chronic mild stress. (CMS-exposed male C57BL/6J mice; 0.5 mg/mL caffeine in drinking water for 6 weeks)
- Setup
- Male C57BL/6J mice (6-7 weeks old) and C2C12 murine myoblast cell line.
- How
- The study used a mouse model of chronic mild stress (CMS) with caffeine supplementation in drinking water and in vitro C2C12 myotube cultures. Analysis included behavioral tests (forced swim, tail suspension), HPLC for plasma metabolites, Western blotting for protein expression, and RT-qPCR for gene expression.
- Limitations
- Caffeine failed to rescue CMS-induced weight loss. · The exact mechanism of how caffeine regulates the proteasomal degradation of PGC-1α remains unclear.
Summarized by Gemma 4 from the open-access full text · 14 Oct 2026. Read it