Abstract

Xiaoyaosan treats depression by activating muscle-brain axis. • XYS restores hippocampal synaptic plasticity via FNDC5/Irisin. • FNDC5/Irisin is an obligatory mediator of muscle-brain crosstalk. • Muscle-brain axis is an integrated therapeutic target for depression. Background The muscle-brain axis is critical in neuropsychiatric disorders. However, its role in the antidepressant mechanism of Xiaoyaosan (XYS) remains unclear. This study explored whether XYS exerts antidepressant effects by modulating the muscle FNDC5/Irisin-mediated muscle-brain axis to restore hippocampal synaptic plasticity. Methods LPS-induced mouse model was established for in vivo evaluation. In vitro, siRNA knockdown in C2C12-HT22 Transwell co-culture system was used to investigate the involvement of FNDC5/Irisin signaling in muscle-neuron communication. Neuromuscular organoids were established as a three-dimensional platform to model key features of muscle-neuron interactions. Untargeted metabolomics, immunohistochemistry, immunofluorescence, Western blotting, and ELISA were performed. Results XYS dose-dependently ameliorated LPS-induced depressive-like behaviors, restored muscle fiber integrity, and reversed hippocampal neuronal loss and synaptic deficits. Metabolomics analysis showed that XYS was associated with normalized metabolite profiles associated with β-alanine and taurine metabolism in the hippocampus and PPAR signaling pathway in the muscle. XYS was also associated with activation of the muscle PPARγ/PGC-1α/FNDC5/Irisin signaling pathway, accompanied by increased circulating Irisin levels and upregulation of hippocampal BDNF, PSD95, and synaptophysin. siRNA knockdown of FNDC5 attenuated the effects of XYS on Irisin secretion and synaptic marker restoration in co-cultured neurons. In organoids, XYS protected both myotube and neuronal compartments from LPS-induced injury. Conclusion XYS exerts antidepressant effects, at least in part, through the activation of the muscle PPARγ/PGC-