Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice.
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 MVo(2)), indicating higher O(2) use for nonmechanical processes such as basal metabolism (MVo(2)(BM)) and excitation-contraction coupling (MVo(2)(ECC)). Although alterations in cardiac metabolism and/or Ca(2+) 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 MVo(2) directly (MVo(2)(unloaded)) and for determining MVo(2)(BM) and MVo(2)(ECC) separately in isolated perfused mouse hearts and 2) determine O(2) cost for these processes in hearts from db/db mice. Unloaded MVo(2), extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and MVo(2), was found to correspond with MVo(2) measured directly in unloaded retrograde perfused hearts (MVo(2)(unloaded)). MVo(2) in K(+)-arrested hearts was defined as MVo(2)(BM); the difference between MVo(2)(unloaded) and MVo(2)(BM) represented MVo(2)(ECC). This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca(2+) concentrations resulted in changes in either MVo(2)(BM) and/or MVo(2)(ECC). The higher MVo(2)(unloaded) in db/db mice was due to both a higher MVo(2)(BM) and MVo(2)(ECC). Elevation of glucose and insulin decreased FA oxidation and reduced both MVo(2)(unloaded) and MVo(2)(BM). In conclusion, this study provides direct evidence that MVo(2)(BM) and MVo(2)(ECC) are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a MVo(2)-lowering effect.
Boardman
Neoma
N
Dept. of Medical Physiology, Institute of Medical Biology, Faculty of Medicine, Univ. of Tromsø, N-9037 Tromsø, Norway. neoma.boardman@uit.no
Hafstad
Anne D
AD
Larsen
Terje S
TS
Severson
David L
DL
Aasum
Ellen
E
D000818:Animals; D001481:Basal Metabolism; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010477:Perfusion; D015203:Reproducibility of Results
D005227:Fatty Acids; D007328:Insulin; D005947:Glucose; D002118:Calcium