Effects of MCC-135 on Ca2+ uptake by sarcoplasmic reticulum and myofilament sensitivity to Ca2+ in isolated ventricular muscles of rats with diabetic cardiomyopathy

Diabetic cardiomyopathy is characterized by delayed cardiac relaxation. Delayed relaxation is suggested to be associated with sarcoplasmic reticulum (SR) dysfunction and/or increase in myofilament sensitivity to Ca2+. Although MCC-135, an intracellular Ca2+-handling modulator, accelerates the delayed relaxation without inotropic effect in the ventricular muscle isolated from rats with diabetic cardiomyopathy, the underlying mechanism has not been fully understood. We tested the hypotheses that MCC-135 modulates Ca2+ uptake by SR and myofilament sensitivity to Ca2+. Wistar rats were made diabetic by a single injection of streptozotocin (40 mg/kg i.v.). Seven months later, the left ventricular papillary muscle was isolated and skinned fibers with and without functional SR were prepared by treatment of the papillary muscle with saponin to study SR Ca2+ uptake and myofilament sensitivity to Ca2+, respectively. In diabetic rats, SR Ca2+ uptake was decreased, which was related to decrease in protein level of SR Ca2+-ATPase determined by western blot analysis. MCC-135 enhanced SR Ca2+ uptake in diabetic rats, but not in normal rats. In diabetic rats, maximum force was decreased but force at diastolic level of Ca2+ was increased, without significant change in myofilament sensitivity to Ca2+ compared with normal rats. MCC-135 decreased force at any pCa tested (pCa 7.0-4.4), but had no significant effect on myofilament sensitivity to Ca2+ in diabetic rats. These results suggest that MCC-135 enhances SR Ca2+ uptake and shifts force-pCa curve downward without modulating myofilament sensitivity to Ca2+. These effects may contribute to positive lusitropic effect without inotropic effect of MCC-135 observed in the ventricular muscle of diabetic cardiomyopathy.