<scp>Alpha‐Asarone</scp> modulates kynurenine disposal in muscle and mediates resilience to stress‐induced depression via <scp>PGC</scp>‐1α induction
Lü Yan, Chuhan Liu, Li Xu, Yiyun Qian, Pingping Song, Min Wei, Baolin Liu
Abstract
Abstract Introduction Kynurenine (KYN) accumulation in periphery induces brain injury, responsible for depression. α‐Asarone is a simple phenylpropanoids that exerts beneficial effects on central nervous system. However, the effect of α‐asarone on periphery is unexplored. Aims Here, we investigated its protective role against depression from the aspect of KYN metabolism in skeletal muscle. Methods The antidepressant effects of α‐asarone were evaluated in chronic mild stress (CMS) and muscle‐specific PGC‐1α‐deficient mice. The effects of KYN metabolism were determined in mice and C2C12 myoblasts. Results α‐Asarone exerted antidepressant effects in CMS and KYN‐challenged mice via modulating KYN metabolism. In myoblasts, α‐asarone regulated PGC‐1α induction via cAMP/CREB signaling and upregulated KYN aminotransferases (KATs) to increase KYN clearance in a manner dependent on PGC‐1α. KAT function is coupled with malate–aspartate shuttle (MAS), while α‐asarone combated oxidative stress to protect MAS and mitochondrial integrity by raising the NAD + /NADH ratio, ensuring effective KYN disposal. In support, the antidepressant effect of α‐asarone was diminished by muscle‐specific PGC‐1α deficient mice subjected to KYN challenge. Conclusion KATs coupled with MAS to clear KYN in muscle. α‐Asarone increased PGC‐1α induction and promoted KYN disposal in muscle, suggesting that protection of mitochondria is a way for pharmacological intervention to depression.