Interval Training Normalizes Cardiomyocyte Function, Diastolic Ca Control, and SR Ca Release Synchronicity in a Mouse Model of Diabetic Cardiomyopathy

Rationale: In the present study we explored the mechanisms behind excitation–contraction (EC) coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db). Objective: We determined whether 13 weeks of aerobic interval training could restore cardiomyocyte Ca cycling and EC coupling. Methods and Results: Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca leak, reduced synchrony of Ca release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca and caffeine-induced Ca release. Additionally, the rate of SR Ca ATPase–mediated Ca uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca release indicated increased Na /Ca -exchanger activity. The increased SR-Ca leak was attributed to increased Ca -calmodulin–dependent protein kinase (CaMKII ) phosphorylation, supported by the normalization of SR-Ca leak on inhibition of CaMKII (AIP). Exercise training restored contractile function associated with restored SR Ca release synchronicity, T-tubule density, twitch Ca amplitude, SR Ca ATPase and Na /Ca -exchanger activities, and SR-Ca leak. The latter was associated with reduced phosphorylation of cytosolic CaMKII . Despite normal contractile function and Ca handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A inhibition (H-89) in cardiomyocytes from the exercised db/db group abolished the differences in SR-Ca load when compared with the sedentary db/db mice. EC coupling changes were observed without changes in serum insulin or glucose levels, suggesting that the exercise training–induced effects are not via normalization of the diabetic condition. Conclusions: These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type. (Circ Res. 2009;105:527-536.)