How muscle talks to brain: apelin protein mediates exercise-induced antidepressant effects

Physical exercise alleviates depressive symptoms and enhances hippocampal plasticity, but the mediators of muscle-brain crosstalk underlying these effects are not fully understood. We evaluated apelin as a novel mediator of the antidepressant effects of physical exercise, specifically testing the hypothesis that exercise-induced increases in skeletal muscle-derived apelin enhance hippocampal plasticity via apelin and its receptor APJ signaling. Voluntary running for 4 weeks alleviated depression-like behaviors and increased serum and hippocampal apelin levels, with skeletal muscles (tibialis anterior and gastrocnemius) as primary apelin sources. Muscle-specific apelin knockout abolished the antidepressant and pro-neurogenic effects of running, whereas muscle‑targeted apelin overexpression mimicked the benefits of running in wild-type mice. Mechanistically, myokine apelin enhanced NMDA receptor-mediated neurotransmission via receptors APJ on hippocampal glutamatergic neurons. Specific knockdown of APJ diminished the pro-neurogenic and antidepressant effects of running. Furthermore, apelin/APJ signaling activated casein kinase 2, which phosphorylated the GluN2B subunit at serine 1480, thereby enhancing NMDA receptor function and activating downstream calpain-2 signaling. Our findings reveal a muscle-brain axis where exercise-induced myokine apelin coordinates hippocampal neuroplasticity and antidepressant responses, offering new therapeutic avenues for depression.