Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart.

Cardiac physiology and pathology have been extensively explored at the transcriptional level. Still, they are less understood at the translational level, including three major knowledge gaps: pathophysiological impact, molecular mechanisms, and therapeutic implications of translational control in cardiac biology and heart disease. This review aims to provide a summary of the most recent key findings in this emerging field of translational control in heart health and disease, covering the physiological functions, disease pathogenesis, biochemical mechanisms, and development of potential RNA-based, translation-manipulating drugs. Translation of mRNA to protein is the final step in the central dogma for protein synthesis. Translation machinery includes a family of essential "housekeeping" factors and enzymes required for mRNA translation. These translation factors ensure the accurate processing of mRNA to protein according to the genetic code and maintain the optimal quality and quantity of cellular proteins for normal cardiac function. Translation factors also regulate the efficiency, speed, and fidelity of protein production and play a role in cardiac pathological remodeling under stress conditions. This review first introduces the techniques and methods used to study the translational regulation of gene expression in the cardiac system. We then summarize discoveries of a variety of pathophysiological functions and molecular mechanisms of translational control in cardiac health and disease, focusing on two primary symptoms, cardiac hypertrophy and fibrosis. In these sessions, we discuss the translational regulation directed by specific regulatory factors in cardiac physiology and how their genetic mutations, expression dysregulation, or functional alterations contribute to the etiology of heart disease. Notably, translational control exhibits extensive crosstalk with other processes, including transcriptional regulation, mitochondrial metabolism, and sarcomere homeostasis. Furthermore, recent findings have revealed the role of translational regulation in cardiomyocyte proliferation and heart regeneration, providing new approaches for creating regenerative medicine. Because transcript-specific translational regulation of both pathological and protective proteins occurs in heart disease, target-selective translation inhibitors and enhancers can be developed. These inhibitors and enhancers offer valuable insights into novel therapeutic targets and the development of RNA-based drugs for heart disease treatment.