Computational analysis of disturbed calcium handling in the diabetic heart

Cardiac function is known to be impaired in diabetes mellitus. The causal chain of events that leads to diabetic cardiomyopathy is incompletely understood. We and others have shown that disturbed calcium homeostasis precedes hemodynamic malfunctioning in streptozotocin-induced diabetic rats. The aim was to investigate the potential role of altered calcium handling on excitation-contraction coupling and mitochondrial energetics. Cyclic changes in cytoplasmic Ca2+i levels were measured in the epicardium of isolated hearts of 4-week Type 1 diabetic rats. A computational 'minimal model' of calcium cycling was applied to infer possible changes in kinetic parameters of the ryanodine receptor and the sarcoplasmic reticulum Ca2+-ATPase by fitting of the experimentally obtained Ca2+i transients. The model predicted that b-adrenergic activation reveals functional derangements of sarcoplasmic reticulum Ca2+ handling in the 4-week diabetic heart. These results were integrated into a novel, detailed model of myocyte energetics, incorporating calcium activated mitochondrial respiration. The excitation-contraction dynamics propagate into the ATP metabolic network and mitochondrial ATP output could be oscillatory. These oscillations interfere with calcium homeostasis given the high sensitivity to ATP free energy potential concomitant with full kinetic reversibility of calcium pumps.