Abstract 17898: Diabetes Promotes a Warburg-like Metabolic Phenotype in Cardiac Stem Cells
Type 2 Diabetes (T2D) is associated with increased mortality and progression to heart failure. While diabetes has been associated with deleterious changes in multiple stem cell populations, the effects of diabetes on cardiac stem cells (CSCs) remain unknown. In this study, we examined the effects of T2D on c-kit+/lin- CSC metabolism and function. Non-diabetic CSCs expressed both the Glut1 and Glut4 transporters and displayed insulin-independent glucose utilization. Compared with differentiated myocytes (CMCs), intact CSCs showed a low mitochondrial membrane potential, yet highly coupled mitochondrial activity (respiratory control ratios: CSCs, 8.4; CMCs, 6). CSCs isolated from diabetic (db/db) mice showed a 50-75% decrease in basal and maximal mitochondrial respiratory capacity (p<0.05), decreased cytochrome oxidase activity and abundance (p<0.05), and an increase in glycolytic flux compared with non-diabetic CSCs (p<0.05). Diabetic CSCs, although resistant to insulin, demonstrated a 3-fold increase in basal Akt phosphorylation (p<0.05) and a 4-fold increase in the abundance of PFKFB3 (p<0.05) an isoform of phosphofructokinase/bisphosphatase-2 that sustains high rates of glycolysis. Upon differentiation, the diabetic CSCs showed a decreased capacity to attain Nkx2.5 positivity and an inability to increase markers of the differentiated state such as α-smooth muscle actin. In vivo, even mild conditions of metabolic syndrome decreased CSC reparative capacity. Wild-type mice fed a high-fat-diet for 12 weeks showed no improvement in myocardial infarction-induced heart failure after CSC transplantation, whereas infarcted, normal chow-fed mice responded normally to CSC therapy (+11% EF, p<0.05). These data indicate that diabetes induces a dormant CSC phenotype, sustained, in part, by high rates of glycolysis and decreased mitochondrial function. This phenotype mirrors the distinctive Warburg metabolic feature of cancer cells and may underlie deficits in stem cell function and reparative capacity in T2D and the metabolic syndrome.
- © 2013 by American Heart Association, Inc.