Table 1.
Summary of recent studies demonstrating a central role for metabolism in heart failure and regeneration.
| Metabolism | Target gene | Function | Application | Results | References |
|---|---|---|---|---|---|
| Fatty acid oxidation | Carnitine palmitoyltransferase 1 (CPT1) | Induces fatty acid oxidation | CPT1 inhibition | Increased proliferation of isolated neonatal cardiomyocytes | (30) |
| Reduced in fatty acid oxidation gene expression | |||||
| No change in adult mouse cardiomyocyte proliferation | (31) | ||||
| Malonyl-CoA decarboxylase (MCD) | Reduces fatty acid oxidation | MCD inhibition | Increased malonyl-CoA levels in ischemic swine heart | (33, 34) | |
| Improved cardiac function following rat heart myocardial infarction (MI) | (35) | ||||
| Increased glucose oxidation in MCD deficient mouse heart | (36) | ||||
| Improved cardiac function in ischemic MCD deficient mouse heart | |||||
| Peroxisome proliferator-activated receptor (PPAR) α | Induces fatty acid oxidation | PPARα activation | Increased CPT1 gene expression and oxygen consumption rate in the presence of the fatty acid palmitate in isolated mouse cardiomyocytes | (30) | |
| No change in adult cardiomyocyte proliferation and cardiac function following MI | (31) | ||||
| Cardiac function decreased following I/R injury | (42) | ||||
| PPARδ | Induces fatty acid oxidation | PPARδ activation | Decreased cardiac fibroblast proliferation and myofibroblast transdifferentiation | (44) | |
| Reduced cardiomyocyte proliferation and increased scar size following MI in mouse heart | (45) | ||||
| PPARδ inhibition | Reduced cardiomyocyte proliferation following cardiac injury in zebrafish | (45) | |||
| Glucose metabolism | GLUT1 | Increases glucose uptake | GLUT1 overexpression | Increased glucose uptake and glycolysis in the mouse heart | (62, 63) |
| Increased regenerative response and glucose metabolites in neonatal mouse heart following cryoinjury | (64) | ||||
| Decreases glucose uptake | GLUT1 inhibition | Reduced glucose uptake and glycolysis in isolated mouse cardiomyocytes following TAC injury | (59) | ||
| Hexokinase (HK) 2 | Increases glycolysis | HK-2 overexpression | Decreased cardiac hypertrophy in isoproterenol-induced mouse hearts | (71) | |
| Reduced cardiomyocyte size in neonatal rat ventricular cardiomyocytes | |||||
| Reduced ROS accumulation | |||||
| Decreases glycolysis | HK-2 inhibition | Increased cardiac dysfunction and cell death and fibrosis | (72) | ||
| Decreased angiogenesis following I/R injury | |||||
| Phosphofructokinase (PFK) 2 | Increases glycolysis | PFK-2 inhibition | Reduced glycolysis and insulin sensitivity in mice | (74, 75) | |
| PFK-2 overexpression | Increased contractility in hypoxic mouse cardiomyocytes | (76) | |||
| Pyruvate dehydrogenase kinase (PDK) | Increases glycolysis | PDK inhibition | Increased cardiac function following KCI-induced cardiac arrest | (77) | |
| PDK-4 inhibition | Promoted mouse cardiomyocyte proliferation and heart regeneration following adult MI | (78) | |||
| Pyruvate kinase muscle isoenzyme 2 (PKM2) | Increases glycolysis | PKM2 overexpression | Increased cardiomyocyte proliferation and cardiac regeneration following adult MI | (79) | |
| PKM2 inhibition | Reduced cardiomyocyte proliferation following injury in zebrafish hearts | (67) | |||
| Impaired heart development and reduced cardiomyocyte proliferation | (79) | ||||
| Amino acid metabolism | Protein Phosphatase 2cm (PP2 cm)/Protein Phosphatase 1 k (PPM1K) | Reduced BCAA oxidation | PP2cm inhibition | Increased BCAA and BCKA levels | (87) |
| Reduced cardiac function and increased heart failure | (87, 89) | ||||
| Decrease in glucose uptake and utilization | (89) | ||||
| Increased BCAA oxidation | PP2cm overexpression | Decreased DNA damage and cell death, leading to a smaller scar size post-MI | (99) | ||
| BCKDK | Increased BCAA oxidation | BCKDK inhibition | Decreased free BCAAs, leading to improved heart function post-TAC | (98) | |
| TCA cycle metabolism | Succinate dehydrogenase (SDH) | Reduced succinate accumulation | SDH inhibition | Reduced infarct size during ischemia in I/R mouse hearts | (106) |
| Reduced infarct size during I/R injury in pig hearts | (107) | ||||
| Induced glucose metabolism in adult mouse hearts | (110) | ||||
| Promoted adult cardiomyocyte proliferation, revascularization, and heart regeneration following MI | (110) |