High-intensity interval training preferentially improves cardiac function via enhanced histone lactylation and macrophage polarization in SAMP8 mice

Aging is associated with progressive cardiac dysfunction, characterized by increased myocardial fibrosis, chronic inflammation, and impaired myocardial structure. Exercise is a well-established, cost-effective intervention for age-related cardiovascular decline, yet the underlying epigenetic mechanisms remain to be fully elucidated. Recent studies have implicated histone lactylation as a regulatory mark that modulates macrophage polarization and inflammatory responses. Histone lactylation, a novel post-translational modification derived from lactate metabolism, has emerged as a key regulator of immune cell polarization and inflammation. Here we investigated the effects of an 8-week intervention using aerobic training, resistance training, and high-intensity interval training (HIIT) on cardiac function and histone lactylation in aging SAMP8 mice. All exercise modalities improved cardiac function and reduced myocardial fibrosis, with HIIT producing the most pronounced effect. Western blot and immunofluorescence analyses revealed elevated levels of histone lactylation (Pan-Kla and H3K18la) and increased M2 macrophage polarization in the exercised groups, along with reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines. These findings suggest that exercise-particularly HIIT-ameliorates age-associated cardiac dysfunction by enhancing histone lactylation and promoting a shift toward anti-inflammatory macrophage polarization, thereby reducing myocardial inflammation and fibrosis. This study provides novel insight into the epigenetic mechanisms of exercise-mediated cardioprotection during aging.