Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice

Abstract

We have reported previously that hearts from type 2 diabetic ( db/ db) mice show decreased cardiac efficiency due to increased work-independent myocardial O2 consumption (unloaded MV̇o2), indicating higher O2 use for nonmechanical processes such as basal metabolism (MV̇o2BM) and excitation-contraction coupling (MV̇o2ECC). Although alterations in cardiac metabolism and/or Ca2+ handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O2 cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded MV̇o2 directly (MV̇o2unloaded) and for determining MV̇o2BM and MV̇o2ECC separately in isolated perfused mouse hearts and 2) determine O2 cost for these processes in hearts from db/ db mice. Unloaded MV̇o2, extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and MV̇o2, was found to correspond with MV̇o2 measured directly in unloaded retrograde perfused hearts (MV̇o2unloaded). MV̇o2 in K+-arrested hearts was defined as MV̇o2BM; the difference between MV̇o2unloaded and MV̇o2BM represented MV̇o2ECC. This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca2+ concentrations resulted in changes in either MV̇o2BM and/or MV̇o2ECC. The higher MV̇o2unloaded in db/ db mice was due to both a higher MV̇o2BM and MV̇o2ECC. Elevation of glucose and insulin decreased FA oxidation and reduced both MV̇o2unloaded and MV̇o2BM. In conclusion, this study provides direct evidence that MV̇o2BM and MV̇o2ECC are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a MV̇o2-lowering effect.