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

Boardman N, Hafstad AD, Larsen TS, Severson DL, Aasum E. Increased O-2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice. Am J Physiol Heart Circ Physiol 296: H1373-H1379, 2009. First published March 13, 2009; doi:10.1152/ajpheart.01264.2008.-We have reported previously that hearts from type 2 diabetic (db/db) mice show decreased cardiac efficiency due to increased work-independent myocardial O-2 consumption (unloaded M(V) over dotO(2)), indicating higher O-2 use for nonmechanical processes such as basal metabolism (M(V) over dotO(2BM)) and excitation-contraction coupling (M(V) over dotO(2ECC)). Although alterations in cardiac metabolism and/or Ca2(+) handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O-2 cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded M(V) over dotO(2) directly (M(V) over dotO(2unloaded)) and for determining M(V) over dotO(2BM) and M(V) over dotO(2ECC) separately in isolated perfused mouse hearts and 2) determine O-2 cost for these processes in hearts from db/db mice. Unloaded M(V) over dotO(2), extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and M(V) over dotO(2), was found to correspond with M(V) over dotO(2) measured directly in unloaded retrograde perfused hearts (M(V) over dotO(2unloaded)). M(V) over dotO(2) in K+-arrested hearts was defined as M(V) over dotO(2BM); the difference between M(V) over dotO(2unloaded) and M(V) over dotO(2BM) represented M(V) over dotO(2ECC). This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca2+ concentrations resulted in changes in either M(V) over dotO(2BM) and/or M(V) over dotO(2ECC). The higher M(V) over dotO(2unloaded) in db/db mice was due to both a higher M(V) over dotO(2BM) and M(V) over dotO(2ECC). Elevation of glucose and insulin decreased FA oxidation and reduced both M(V) over dotO(2unloaded) and M(V) over dotO(2BM). In conclusion, this study provides direct evidence that M(V) over dotO(2BM) and M(V) over dotO(2ECC) are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a M(V) over dotO(2)-lowering effect.