Alteration of the phosphocreatine energy shuttle components in diabetic rat heart.
Considering the important role of the phosphocreatine energy shuttle in contractile function of the heart we decided to study the different components of this shuttle in STZ-induced diabetic rat heart with a known diabetic related cardiomyopathy. Diabetes produced a gradual decline in total CK activity, reaching a maximum of 35-40% decrease after 4 weeks of diabetes, in both atria and ventricles. All of the CK isoenzymes including the mitochondrial CK (CKm) were reduced but to a different extent in these two tissues. The percentage reduction in diabetic ventricles was BB greater than MB greater than CKm greater than MM and in atria was CKm greater than BB greater than MB greater than MM. A major difference between atrium and ventricle was the greater loss of CKm in diabetic atria than diabetic ventricle (75% in atria vs 32% in ventricle). The B subunit seemed to be the one that was affected the most followed by CKm isoenzyme and then the M subunit. The bound myofibrillar CK isoenzyme, expressed as units of activity/mg of myofibrillar protein, was not affected by 4 weeks of diabetes. The high energy phosphates were also reduced in diabetic heart with a greater reduction in phosphocreatine (43-45%) and a smaller change in ATP (27%). Mitochondrial oxidative phosphorylation with alpha-ketoglutarate was reduced (55%) in diabetic heart, whereas, there was no difference when succinate was used as substrate. These changes were reversible by 4 weeks of insulin treatment. The loss of CKm, phosphocreatine and the reduction in mitochondrial oxidative phosphorylation, could result in an inefficient phosphocreatine energy shuttle which could contribute to the cardiac functional defects associated with diabetes.
Savabi
F
F
University of Southern California, School of Medicine, Department of Pharmacology and Nutrition, Los Angeles 90033.
Kirsch
A
A
D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004734:Energy Metabolism; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010725:Phosphocreatine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D007328:Insulin; D007527:Isoenzymes; D010725:Phosphocreatine; D003402:Creatine Kinase