Unravelling the Interplay between Cardiac Metabolism and Heart Regeneration

Abstract

Ischemic heart disease (IHD) is the leading cause of heart failure (HF) and is a significant cause of morbidity and mortality globally. An ischemic event induces cardiomyocyte death, and the ability for the adult heart to repair itself is challenged by the limited proliferative capacity of resident cardiomyocytes. Intriguingly, changes in metabolic substrate utilisation at birth coincide with the terminal differentiation and reduced proliferation of cardiomyocytes, which argues for a role of cardiac metabolism in heart regeneration. As such, strategies aimed at modulating this metabolism-proliferation axis could, in theory, promote heart regeneration in the setting of IHD. However, the lack of mechanistic understanding of these cellular processes has made it challenging to develop therapeutic modalities that can effectively promote regeneration. Here, we review the role of metabolic substrates and mitochondria in heart regeneration, and discuss potential targets aimed at promoting cardiomyocyte cell cycle re-entry. While advances in cardiovascular therapies have reduced IHD-related deaths, this has resulted in a substantial increase in HF cases. A comprehensive understanding of the interplay between cardiac metabolism and heart regeneration could facilitate the discovery of novel therapeutic targets to repair the damaged heart and reduce risk of HF in patients with IHD.

Keywords: angiogenesis; cardiac metabolism; cardiac progenitor cells; cardiomyocyte proliferation; heart failure; heart regeneration; hormones; ischemic heart disease; mitochondria; reactive oxygen species.

Figure 1

Schematic illustrating the interplay between cardiac metabolism and cardiomyocyte proliferation in neonatal and adult mammalian hearts. Neonatal heart metabolism (red), adult heart metabolisms (blue). Abbreviations: Glut1—glucose transporter type 1; Glut4—glucose transporter type 4; PK—pyruvate kinase; PDK—pyruvate dehydrogenase kinase; FACS—fatty acyl coA synthase; PPARα—peroxisome-proliferator-activated receptor alpha; BCAAs—branched-chain amino acids; BCKA—branch-chain alpha-keto acids; mTORC1—mammalian target of rapamycin complex 1; TCA—tricarboxylic acid cycle.

Figure 2

Schematic illustrating the role of mitochondria in cardiac injury and regeneration. (Left) environmental stress, such as that caused by ischemia/reperfusion injury can lead to mitochondrial dysfunction, resulting in ROS overproduction and dysregulation of mitochondrial dynamics, thereby instigating DNA damage and suppressing cardiomyocyte proliferation. (Right) under hypoxic conditions or during antioxidant treatments, cardiomyocytes can switch from oxidative metabolism to glycolysis, potentially via the HIF-1α pathway, and undergo restoration of aberrant mitophagy and mitochondria biogenesis to promote cell cycle re-entry. Abbreviations: ROS—reactive oxygen species; HIF-1α—hypoxia inducible factor 1α.