Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart.
The objective of this study was to determine whether a defect in mitochondrial respiratory function accompanies the development of diabetic cardiomyopathy. The hypothesis tested in this study is that a decrease in Ca2+ uptake into mitochondria may prevent the stimulation of Ca(2+)-sensitive matrix dehydrogenases and the rate of ATP synthesis. Streptozotocin (55 mg/kg)-induced diabetic rats were used as a model of insulin-dependent diabetes mellitus. Hearts from 4-wk diabetic rats had basal heart rates and rates of contraction and relaxation similar to control. Isoproterenol caused a similar increase in the rate of contraction in diabetic and control hearts, whereas the peak rate of relaxation was reduced in diabetic hearts. Mitochondrial Ca2+ uptake was reduced in mitochondria from diabetic hearts after 2 wk of diabetes. Na(+)-induced Ca2+ release was unchanged. State 3 respiration rate was depressed in mitochondria from diabetic rats only when the respiration was supported by the substrate of a Ca(2+)-regulated matrix enzyme. The pyruvate dehydrogenase activity was reduced in diabetic mitochondria compared with that of control. It was concluded that mitochondria from diabetic hearts had a decreased capacity to upregulate ATP synthesis via stimulation of Ca(2+)-sensitive matrix dehydrogenases. The impairment in the augmentation of ATP synthesis rate accompanies a decreased rate of relaxation during increased work load.
Flarsheim
C E
CE
Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Ohio 45267, USA.
Grupp
I L
IL
Matlib
M A
MA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003971:Diastole; D005227:Fatty Acids / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000502:physiology
D005227:Fatty Acids; D007328:Insulin; D012964:Sodium; D007545:Isoproterenol; D002118:Calcium