Metabolic regulation of cardiac regeneration: roles of hypoxia, energy homeostasis, and mitochondrial dynamics

Abstract

The adult mammalian heart cannot regenerate after myocardial injury because most cardiomyocytes lack the ability to proliferate. In contrast, cardiomyocytes of vertebrates such as zebrafish and urodele amphibians, but also those of fetal and early neonatal mammals, maintain the ability to proliferate and therefore support regeneration of injured tissue and recovery of cardiac function. Whether evolutionarily conserved regulatory mechanisms of cardiomyocyte proliferation exist and, if so, whether they are modifiable to allow cardiac regeneration in adult mammals are questions of great scientific and medical interest. Environmental hypoxia, hypoxia-induced cellular signaling, and mitochondrial metabolism have recently emerged as key regulators of the cardiomyocyte cell cycle and cardiac regeneration in vertebrates. In this review, we address the cardiac regenerative capacity of several model animals and discuss potential strategies related to hypoxia and mitochondrial metabolism for induction of therapeutic heart regeneration.