Reversed Ryr-Leakage And Improved Contractile Function In Cardiomyocytes From Type-2 Diabetic Heart After Exercise Training

PURPOSE: The db/db type-2 diabetes mouse model exhibits decreased cardiac performance both in isolated working hearts and in isolated cardiomyocytes. Increased diastolic SR Ca2+ leak from ryanodine receptors (RyR) have been proposed to be the mechanism behind depressed contractility in the diabetic heart. In this study, contractile performance and calcium handling was studied in isolated cardiomyocytes in both trained and sedentary db/db as well as in wild-type control mice. METHODS: Twelve male db/db mice were randomized to sedentary control or regular interval training on a treadmill for 12 weeks, 5 days/week, 1.5 hours/day, at 85–90% of maximal oxygen uptake (VO2max). Six wild-type mice served as normal controls. Single cardiomyocytes from the left ventricle were isolated using collagenase. Cardiomyocytes were stimulated (1Hz) on an inverted epi-fluorescence microscope. SR Ca2+ leakage was determined using tetracaine and caffeine. RESULTS: VO2max increased 20% (from 57±4 to 68±6 ml/kg/min) in trained db/db-mice, whereas a 8% reduction was observed in sedentary controls (p<0.01). Cardiomyocyte fractional shortening (3.5±1.6 % vs. 8.4±2.3 %) and calcium amplitude (Fura-2 ratio 0.07±0.02 vs. 0.15±0.03) was lower, the rate of Ca2+ decay 47% slower, and Ca2+ leakage (normalized to total SR Ca2+ load) significantly higher (31 % vs. 7%) in db/db mice compared with wild-type controls (p<0.05). Endurance training restored fractional shortening (7.8±0.4%), Ca2+ amplitude (Fura-2 ratio 0.12), and Ca2+ decay to a level not significant from wild-type controls. In trained db/db mice, Ca2+ leakage from RyR (9%) was similar to that observed in wild-type mice, and probably explains increased SR Ca2+ content and increased calcium amplitude. Furthermore, improved Ca2+ decay was due to increased activity of the SR- Ca2+ pump and not increased sodium-calcium exchanger activity. CONCLUSIONS: Endurance training improves cardiomyocyte function in diabetes type-2 mice by increasing the amount of calcium available for contraction through reduced RyR-leakage and increased SR- Ca2+ pump activity.