Lactylation: A Potential Mechanism Linking Exercise Regimens to Macrophage Polarization and Cardiac Repair after Myocardial Infarction – A Narrative Review

Myocardial infarction (MI) is a leading global health challenge necessitating therapeutic interventions, such as cardiac rehabilitation (CR), to mitigate adverse cardiac remodeling and restore functional capacity. Exercise-based CR, a cornerstone of post-MI management, significantly improves cardiovascular outcomes, likely owing to the stimulation of macrophage activity. Macrophages play a pivotal role in post-MI inflammatory and reparative phases because of their phenotypic plasticity. Lactate is a key molecule involved in phenotypic shifts in macrophages. Traditionally viewed as a metabolic byproduct, lactate has recently been identified as a crucial signaling molecule and substrate for lactylation, a post-translational modification involving covalent attachment to lysine residues on histones and non-histone proteins. This epigenetic modification directly links cellular metabolism to gene expression and protein function. Emerging evidence indicates that exercise profoundly influences lactate dynamics and lactylation events in various tissues, including heart and immune cells. In this review, the current knowledge on the intricate interplay between exercise, lactate metabolism, lactylation, and macrophage function in MI is summarized. Furthermore, we propose a novel mechanistic framework in which different exercise regimens enhance macrophage pro-reparative polarization and functional reprogramming to promote cardiac repair by modulating lactate availability and specific lactylation events. The molecular mechanisms underlying lactylation, its known roles in macrophage biology, and how exercise-induced metabolic shifts can leverage this pathway to foster a pro-reparative cardiac microenvironment have been critically examined in the current literature. Furthermore, significant research gaps are highlighted, and future directions for investigating lactylation as a therapeutic target to optimize macrophage-mediated CR strategies post-MI are suggested.