Cardiac Regeneration in Adult Zebrafish: A Review of Signaling and Metabolic Coordination

This review investigates how post-injury cellular signaling and energy metabolism are two pivotal points in zebrafish's cardiomyocyte cell cycle re-entry and proliferation. It seeks to highlight the probable mechanism of action in proliferative cardiomyocytes compared to mammals and identify gaps in the current understanding of metabolic regulation of cardiac regeneration.

Metabolic substrate changes after birth correlate with reduced cardiomyocyte proliferation in mammals. Unlike adult mammalian hearts, zebrafish can regenerate cardiomyocytes by re-entering the cell cycle, characterized by a metabolic switch from oxidative metabolism to increased glycolysis. Zebrafish provide a valuable model for studying metabolic regulation during cell cycle re-entry and cardiac regeneration. Proliferative cardiomyocytes have upregulated Notch, hippo, and Wnt signaling and decreased ROS generation, DNA damage in different zebrafish cardiac regeneration models. Understanding the correlation between metabolic switches during cell cycle re-entry of already differentiated zebrafish cardiomyocytes is being increasingly recognized as a critical factor in heart regeneration. Zebrafish studies provide insights into metabolic adaptations during heart regeneration, emphasizing the importance of a metabolic switch. However, there are mechanistic gaps, and extensive studies are required to aid in formulating therapeutic strategies for cardiac regenerative medicine.