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.

BACKGROUND: Coronary microvascular hyperpermeability and the subsequent inflammation infiltration are the key early characteristics of pressure overload–induced myocardial injury. However, how changes in the coronary endothelial barrier function in response to cardiac pressure overload are less explored. Here, we investigated the specific role of S1PR1 (sphingosine-1-phosphate receptor type 1) on coronary endothelial permeability and the signaling pathways involved during pressure overload. METHODS: Mice with endothelial deletion of S1PR1 or MYPT1 (myosin phosphatase target subunit 1) were subjected to transverse aortic constriction. We also studied cultured human umbilical vein endothelial cells (ECs) in vitro. RESULTS: We found upregulated S1PR1 in cardiac ECs at 24 hours and 3 days after transverse aortic constriction, and EC-specific deletion of S1PR1 ( S1pr1 ^{Δ EC} ) led to coronary endothelial hyperpermeability, myocardial edema, and inflammatory infiltration in mice subjected to transverse aortic constriction. In cultured human umbilical vein ECs, silencing S1PR1 reduced total MYPT1 but increased phosphorylated MYPT1, and under TNF-α (tumor necrosis factor-α) stimulation led to MLC (myosin light chain) phosphorylation and actin cytoskeletal contraction. Although S1PR1-NFATc2 (Nuclear Factor of Activated T Cells 2) signaling was essential for maintaining MYPT1 expression, S1PR1 deficiency increased TRPV4 (transient receptor potential vanilloid 4) expression, enhancing extracellular Ca ²⁺ entry and MYPT1 phosphorylation. Mice with EC–specifically MYPT1-deficient ( Mypt1 ^{Δ EC} ) also showed coronary endothelial hyperpermeability, and treatment with the S1PR1 agonist FTY720 failed in alleviating the pathological effects. At 1 month post–transverse aortic constriction, both Mypt1 ^{Δ EC} and S1pr1 ^{Δ EC} mice displayed aggravated pathological cardiac remodeling. CONCLUSIONS: These findings suggest that the S1PR1-MYPT1 signaling is crucial for coronary endothelial permeability and myocardial microenvironmental homeostasis under pressure overload, targeting which may offer therapeutic potential for related heart diseases.

BACKGROUND: Cardiac reserve is a strong predictor of cardiovascular morbidity and mortality, yet the metabolic mechanisms that enable the heart to mount an adaptive response to stress remain poorly understood. In this study, we sought to dissect the specific role of glutaminolysis, a key anaplerotic and redox-supporting pathway, in regulating cardiac reserve. METHODS: Cardiac reserve was assessed by echocardiography under β-adrenergic stimulation in mice with cardiomyocyte-specific deletion of glutaminase and in wild-type controls. Stable isotope tracing with [U- ¹³ C] glutamine was performed in Langendorff-perfused hearts. A randomized, double-blind, placebo-controlled crossover trial of acute glutamine supplementation in healthy volunteers was conducted to evaluate translational relevance (ChiCTR2400082676). RESULTS: During acute stress, such as exercise or β-adrenergic stimulation, glutaminolysis was rapidly mobilized to supply mitochondrial glutathione, preserving mitochondrial redox homeostasis and sustaining cardiac contractile reserve. Mice with cardiomyocyte-specific deletion of glutaminase exhibited marked impairments in both contractile reserve and exercise capacity, accompanied by a failure to elevate mitochondrial glutathione and consequent mitochondrial oxidative stress. Chronic exercise training upregulated cardiac glutaminase expression and expanded the mitochondrial glutathione pool, linking this adaptive mechanism to training-induced improvements in cardiac reserve. In humans, acute oral glutamine supplementation enhanced cardiac reserve, as assessed by exercise stress echocardiography, in a placebo-controlled crossover design. CONCLUSIONS: These findings reveal a novel metabolic paradigm in which glutaminolysis functions as a dynamic pathway supporting mitochondrial health and cardiac resilience, and highlight glutamine supplementation as a potential therapeutic strategy to enhance cardiac reserve.