Exercise-induced histone lactylation in monocyte-derived macrophages restores cardiac immune homeostasis and function in sepsis-induced cardiomyopathy

Abstract An active lifestyle protects against cardiovascular diseases, yet its mechanisms in modulating the cardiac immune environment and preserving cardiac function remain unclear. Here, we identify a subpopulation of monocyte-derived cardiac macrophages, termed iNOS + Arg1 + macrophages, which simultaneously express pro-inflammatory and pro-reparative genes in exercised male mice. Inhibiting either pro-inflammatory iNOS or pro-reparative Arg1 in these macrophages counters the exercise-induced cardiac function preservation. Mechanistically, exercise enhances glycolysis in monocytes, increasing lactate production and driving histone lactylation at H3K18, mediated by p300 as the relevant lactyltransferase and counterbalanced by HDAC2 as deacetylase. H3K18la accelerates the transition of cardiac macrophages to a pro-reparative state, restoring immune homeostasis and preserving cardiac function. Notably, human monocytes from physically active individuals exhibit elevated levels of Pan-Kla and H3K18la compared to those from sedentary individuals. Importantly, adoptive transfer of highly histone-lactylated monocytes restores cardiac function in sepsis-induced cardiomyopathy, which might translate into a promising therapeutic strategy for cardiomyopathy.