Abstract
Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.
Highlights
Heart failure is the leading cause of morbidity and mortality worldwide
Ventricular cardiomyocytes isolated from neonatal mice injected with the CPT1 inhibitor etomoxir show a reduction in fatty acid oxidation genes [30]. These results demonstrate that disruption of fatty acid oxidation by inhibition of CPT1 extends neonatal cardiomyocyte proliferation and heart regeneration but is not sufficient to promote adult heart regeneration
These results demonstrate that Succinate dehydrogenase (SDH) inhibition by malonate promotes adult heart regeneration via metabolic reprogramming [110]
Summary
Heart failure is the leading cause of morbidity and mortality worldwide. In the United States alone, there are over 6,000,000 people with heart failure [1]. These results demonstrate that disruption of fatty acid oxidation by inhibition of CPT1 extends neonatal cardiomyocyte proliferation and heart regeneration but is not sufficient to promote adult heart regeneration. MCD deficient mouse hearts show increased glucose oxidation and improved cardiac function following I/R injury [36]. The PPARα agonist GW7647 does not promote cardiomyocyte proliferation and cardiac function following MI in adult mouse hearts [31].
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