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

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 () and Feng Gao ()
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Nini Zhang: Fourth Military Medical University
Xinpei Wang: Fourth Military Medical University
Mengya Feng: Fourth Military Medical 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
Feng Gao: Fourth Military Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47458-3

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