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

Medicine and Health

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

N. Zhang, X. Wang, et al.

Discover how early-life regular exercise can enhance anti-inflammatory immunity in middle-aged male mice through innovative epigenetic immunometabolic modulation. This research, conducted by 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, reveals lasting immunomodulatory benefits tied to exercise habits developed in youth.

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Playback language: English
Introduction
Regular physical activity offers numerous health benefits, including improved immune function and protection against infections. Epidemiological studies link regular exercise to reduced mortality and infection rates, including COVID-19. Exercise mitigates chronic inflammation, a factor in immune suppression and increased susceptibility to infection. However, research on the long-term impact of early-life exercise on immune function is surprisingly limited, despite evidence suggesting that early childhood physical activity influences adult health outcomes. The close relationship between metabolism and immunity, known as immunometabolism, is increasingly recognized. Exercise alters metabolic pathways, particularly lipid and amino acid metabolism, and specific metabolites influence immune function. While acute exercise impacts metabolites like lactate and succinate, the long-term effects on circulating metabolites and immune function remain poorly understood. This study investigates the long-term impact of early-life exercise training on immune function in male mice, focusing on the potential role of immunometabolic changes and epigenetic modifications.
Literature Review
Existing research highlights the numerous short-term benefits of exercise on immune health, such as improved fitness, cardiovascular health, and overall well-being. Chronic exercise training positively modulates immune function, providing protection against infections. Epidemiological studies demonstrate correlations between physical activity and reduced mortality from various infections. Regular exercise has been shown to mitigate chronic inflammation, which can impair immune function. However, there's a gap in the literature regarding the long-term effects of early-life exercise on immune function and its influence on combating infections later in life. The field of immunometabolism has emerged, revealing the interconnectedness of metabolism and immunity. Studies show that moderate-to-vigorous exercise triggers metabolic responses, particularly affecting lipid and branched-chain amino acid pathways. These metabolic shifts can enhance insulin sensitivity and reduce type 2 diabetes risk. Specific metabolites are known to regulate immune function; for example, lactate influences both pro- and anti-inflammatory responses, and succinate triggers inflammatory reactions. While acute exercise effects on metabolites like lactate and succinate are known, the long-term consequences remain largely unexplored.
Methodology
This study used a male C57BL/6J mouse model. One-month-old mice were subjected to a 3-month swimming training program (Exe mice), while age-matched controls remained sedentary (Sed mice). After an 11-month detraining period, both groups were challenged with a sublethal dose of LPS to induce sepsis. Sepsis severity was assessed using a murine sepsis score (MSS) encompassing various clinical parameters (spontaneous activity, response to stimuli, posture, respiration, appearance). Body weight, temperature, and blood glucose were also monitored. Complete blood cell counts and cytokine levels (TNF, IL-1β, IL-1Ra) were measured. Liver and lung tissues were examined histopathologically for inflammation and damage. Untargeted metabolomics profiling was conducted on serum and liver samples from both groups at 4 and 15 months of age using LC-MS. Targeted LC-MS/MS was used to validate pipecolic acid levels. The effect of pipecolic acid administration on sepsis was investigated in a separate group of mice. BMDMs were isolated and treated with LPS and varying concentrations of pipecolic acid to assess its anti-inflammatory effects. RNA sequencing and Western blotting were performed to explore underlying mechanisms, particularly mTORC1 signaling. To investigate the role of Crym, a liver enzyme involved in pipecolic acid production, 14-month-old mice were injected with AAV8 carrying either Crym-shRNA or scramble-shRNA. DNA methylation and histone modification analyses (H3K4me3) were conducted to explore epigenetic mechanisms regulating Crym expression. Primary hepatocytes were isolated and used for ChIP-seq, ChIP-qPCR, and studies on Setd1a.
Key Findings
Early-life exercise significantly reduced LPS-induced sepsis severity and improved recovery in middle-aged mice, even after a long detraining period. Pipecolic acid levels were consistently elevated in the serum and liver of exercised mice at both 4 and 15 months of age. Pipecolic acid administration reduced LPS-induced inflammation and sepsis in mice, improving recovery. Pipecolic acid inhibited mTORC1 signaling in LPS-stimulated macrophages, reducing pro-inflammatory cytokine production. Early-life exercise increased H3K4me3 levels at the Crym promoter in the liver, a key enzyme in pipecolic acid synthesis. Liver-specific Crym knockdown abolished the protective effects of early-life exercise. Both acute and chronic exercise in humans also increased circulating pipecolic acid levels. Increased Setd1a expression was observed in the liver of exercised mice, potentially contributing to H3K4me3 modification at the Crym promoter. In vitro experiments confirmed that SETD1A overexpression increased H3K4me3 and Crym expression, while knockdown reduced them.
Discussion
This study reveals a novel mechanism by which early-life exercise confers long-term protection against inflammation and sepsis. The sustained elevation of pipecolic acid, driven by epigenetic modification at the Crym promoter, is central to this effect. Pipecolic acid's anti-inflammatory action through mTORC1 inhibition provides a mechanistic explanation for the observed protection. The findings align with previous research showing the beneficial impact of exercise on immune function, but extends this knowledge by demonstrating the long-term effects of early-life intervention and identifying a key mediating metabolite and epigenetic mechanism. The observed increase in pipecolic acid in both acute and chronic human exercise scenarios suggests translational relevance of these findings.
Conclusion
This study demonstrates that early-life regular exercise significantly enhances anti-inflammatory immunity in middle-aged male mice through epigenetic regulation of immunometabolic pathways, with pipecolic acid playing a crucial role. The sustained increase in hepatic pipecolic acid production, driven by H3K4me3 modification at the Crym promoter, provides a long-term protective effect against LPS-induced sepsis. This work highlights the substantial long-term benefits of early-life physical activity on immune health and warrants further investigation into the potential of pipecolic acid as a therapeutic target.
Limitations
This study used a mouse model, limiting the direct applicability to humans. While human data shows increased pipecolic acid after exercise, further research is needed to confirm the long-lasting immune benefits in humans. The sepsis model used LPS rather than live pathogens, neglecting the complexity of polymicrobial sepsis and host-pathogen interactions. While the involvement of Setd1a-mediated H3K4me3 modification in increased Crym expression was suggested, further research is needed to definitively establish the causal relationship.
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