Properties of Calcium Transients in Cardiomyocytes with Impaired Insulin Signaling

Abstract

Diabetes is a major risk factor for cardiovascular diseases, including cardiac arrhythmias, heart failure and sudden cardiac death. In animal models of diabetes, cardiac calcium handling is severely impaired. However, as diabetes is a multifactorial disease it is difficult to separate the effect of systemic and local factors in disease development. Here, we investigate the effect of locally disrupted cardiac insulin signaling on cardiac calcium handling in a mouse model of diabetic cardiomyopathy.We measured calcium transients in isolated cardiomyocytes from Cardiac Insulin Receptor Knock-Out (CIRKO) mice. Littermate wild-type (WT) mice were used as controls. Cardiomyocytes were field stimulated and intracellular calcium was monitored using the fluorescent indicator fluo2-LeakRes (34oC, pHo 7.4, [Ca2+]o = 1.0 mM). Calcium transient amplitude and decay kinetics were measured at 1 and 5 Hz. While no significant differences were observed between WT and KO cardiomyocytes, there was a tendency towards reduced calcium transient amplitude in the KO group (Amplitude (F/F0): WT, 1.6±0.7 (n=9); KO, 1.0±0.4 (n=16); p=0.05). Calcium transient decay was similar (tau (ms): WT, 183±44 (n=9); KO: 232±84 (n=17); p=0.15) and frequency-dependent acceleration of decay kinetics was observed in both groups (tau: p<0.01 for both WT and KO (1Hz vs 5 Hz)).In conclusion, at the cellular level the CIRKO mouse model of diabetic cardiomyopathy display a very mild calcium handling phenotype. These findings suggest that impaired cardiac insulin signaling per se plays only a minor role in the contractile dysfunction observed in systemic models of diabetes.