Mitochondrial Ca 2+ uptake affects contractile properties in streptozotocin-induced diabetic rat myocardium

Background: Diabetes mellitus is a major risk factor for the development of heart failure. However, the role of mitochondrial Ca ²⁺ in regulating contractile function in diabetic myocardium has not been fully elucidated. In the present study, we examined how mitochondrial Ca ²⁺ uptake influences myocardial contractile properties under diabetic conditions. Methods and Results: Rats were injected with 55 mg/kg streptozotocin (STZ rats) or solvent (Ctr rats). Six weeks after the injection, trabeculae were dissected from the right ventricles. Force was recorded with a strain gauge, intracellular Ca ²⁺ with fura-2, reactive oxygen species (ROS) production with MitoSOX Red, and mitochondrial Ca ²⁺ with rhod-2 in trabeculae. The maximal velocity of contraction (dF/dt _max ) and the minimal velocity of relaxation (dF/dt _min ) were normalized to the amplitude of developed force (Force _peak ) at 0.7 and 2.0 mM extracellular Ca ²⁺ . Blood glucose levels were higher in STZ rats than in Ctr rats. STZ rats exhibited reduced Force _peak , smaller dF/dt _max /Force _peak , smaller dF/dt _min /Force _peak , and a lower peak of intracellular Ca ²⁺ transients with a slower decay compared with Ctr rats. Both mitochondrial calcium uniporter (MCU) expression and MitoSOX Red fluorescence were elevated in STZ rats. In STZ rats, Ru360, an MCU inhibitor, decreased rhod-2 and MitoSOX Red fluorescence and increased both dF/dt _max /Force _peak and dF/dt _min /Force _peak . In contrast, spermine increased rhod-2 fluorescence but decreased dF/dt _max /Force _peak and dF/dt _min /Force _peak . Conclusions . Mitochondrial Ca ²⁺ uptake modulates myocardial contractile properties through altered ROS production at a relatively early stage of diabetes.