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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月14日

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  • Jiasui Yu,
  • Tong Cheng,
  • Huihui Guo,
  • Zhiping Song,
  • Yunxiao Zhong,
  • Thomas Ho-yin Lee,
  • Jiyang Li,
  • Douglas A. Formolo,
  • Akhlaq Hussain,
  • Kai Le,
  • Yuxuan Yao,
  • Richard L. Abel,
  • Wing-Hoi Cheung,
  • Kangguang Lin,
  • Aimin Xu,
  • Kenneth King-Yip Cheng,
  • Suk-Yu Yau

摘要

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.