Long-term exercise-derived exosomal CRNDE is linked to GLUT4-dependent lactate production and histone lactylation during myocardial infarction injury.

BACKGROUND AND

OBJECTIVE

Histone lactylation drives reparative macrophage responses after myocardial infarction. Our recent study identified exosomal CRNDE as a key mediator of exercise-induced cardioprotection. Given the role of CRNDE in glycolysis, the present study aimed to explore whether exercise-derived exosomes (exe-exo) alleviate myocardial injury by modulating inflammation through histone lactylation.

METHODS

Myocardial ischemia/reperfusion (I/R) mice were treated with long-term sedentary or exercise-derived exosomes, with or without CRNDE silencing. Cardiac inflammation and macrophage infiltration were evaluated, and pan-lactylation and H3K18 lactylation levels were assessed in bone marrow and circulating monocytes. In vitro, LPS-stimulated BMDMs received exe-exo, either alone or combined with FX-11 or GLUT4 knockdown. Lactate production and macrophage polarization were assessed, and conditioned media were applied to evaluate endothelial functional responses. GLUT4 dependency was further confirmed in vivo using GLUT4-deficient I/R mice.

RESULTS

Exe-exo suppressed cardiac inflammation after I/R and concomitantly enhanced pan-lactylation and H3K18 lactylation in bone marrow and circulating monocytes. CRNDE silencing abolished the anti-inflammatory effects and lactylation increase induced by exe-exo. In BMDMs, exe-exo enhanced lactate production, H3K18 lactylation, and reparative-like macrophage responses, which were attenuated by FX-11. GLUT4 was identified as a key mediator of exe-exo action. GLUT4 knockdown abolished exe-exo-induced lactate production, H3K18 lactylation, and macrophage-driven pro-angiogenic effects in vitro. Consistently, GLUT4 deficiency markedly attenuated exe-exo-mediated cardioprotection in vivo.

CONCLUSION

Exe-exo alleviates myocardial I/R injury by activating a GLUT4-dependent glycolysis-lactate-H3K18 lactylation axis in monocytes and macrophages, thereby coordinating inflammation resolution and angiogenesis.