Limited Heart Rate Reduction Promotes Cardiac Regeneration Through Stimulation of the Metabolic Pattern Switch

As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. The myocardial energy metabolism was recently reported to be related to the loss of proliferation capacity in cardiomyocyte (CM). However, the intrinsic relationship between beating rate and proliferation in CM and whether energy metabolism can regulate this relationship is not known. In this study, we found that limited HRR induced CM proliferation under physiological conditions and promoted cardiac regenerative repair after myocardial injury. Mechanistically, limited HRR induced G1/S transition and increased the expression of glycolytic enzyme in CMs. Furthermore, limited HRR induced a unique metabolic pattern switch (activating glucose metabolism and increased the relative proportion of ATP production by the glycolytic pathway) for the biosynthesis of substrates needed for proliferative CM. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restore.