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Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice

Author

Listed:
  • Nini Zhang

    (Fourth Military Medical University
    Fourth Military Medical University)

  • Xinpei Wang

    (Fourth Military Medical University)

  • Mengya Feng

    (Fourth Military Medical University
    Xi’an Jiaotong University)

  • Min Li

    (Fourth Military Medical University)

  • Jing Wang

    (Fourth Military Medical University)

  • Hongyan Yang

    (Fourth Military Medical University)

  • Siyu He

    (Fourth Military Medical University)

  • Ziqi Xia

    (Fourth Military Medical University)

  • Lei Shang

    (Fourth Military Medical University)

  • Xun Jiang

    (Fourth Military Medical University)

  • Mao Sun

    (Fourth Military Medical University)

  • Yuanming Wu

    (Fourth Military Medical University)

  • Chaoxue Ren

    (Xi’an Physical Education University)

  • Xing Zhang

    (Fourth Military Medical University)

  • Jia Li

    (Fourth Military Medical University
    Fourth Military Medical University)

  • Feng Gao

    (Fourth Military Medical University)

Abstract

Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function.

Suggested Citation

  • Nini Zhang & Xinpei Wang & Mengya Feng & Min Li & Jing Wang & Hongyan Yang & Siyu He & Ziqi Xia & Lei Shang & Xun Jiang & Mao Sun & Yuanming Wu & Chaoxue Ren & Xing Zhang & Jia Li & Feng Gao, 2024. "Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47458-3
    DOI: 10.1038/s41467-024-47458-3
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    References listed on IDEAS

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    1. Matthew J. Yousefzadeh & Rafael R. Flores & Yi Zhu & Zoe C. Schmiechen & Robert W. Brooks & Christy E. Trussoni & Yuxiang Cui & Luise Angelini & Kyoo-A Lee & Sara J. McGowan & Adam L. Burrack & Dong W, 2021. "An aged immune system drives senescence and ageing of solid organs," Nature, Nature, vol. 594(7861), pages 100-105, June.
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