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ABSTRACT: In the present study we explored the mechanisms behind excitation-contraction (EC)-coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db), and determined whether 13-weeks of aerobic interval training could restore cardiomyocyte Ca<sup>2+</sup> cycling and EC-coupling. Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca<sup>2+</sup> leak, reduced synchrony of Ca<sup>2+</sup> release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca<sup>2+</sup> and caffeine-induced Ca<sup>2+</sup> release. Additionally, the rate of SR Ca<sup>2+</sup> ATPase (SERCA2a)-mediated Ca<sup>2+</sup> uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca<sup>2+</sup> release indicated increased Na<sup>+</sup>/Ca<sup>2+</sup>- exchanger (NCX) activity. The increased SR-Ca<sup>2+</sup> leak was attributed to increased Ca<sup>2+</sup>-calmodulindependent protein kinase (CaMKIIδ) phosphorylation, supported by the normalization of SR-Ca<sup>2+</sup> leak upon inhibition of CaMKIIδ (AIP). Exercise training restored contractile function associated with restored SR Ca<sup>2+</sup> release synchronicity, T-tubule density, twitch Ca<sup>2+</sup> amplitude, SERCA2a and NCX activities, and SR-Ca<sup>2+</sup> leak. The latter was associated with reduced phosphorylation of cytosolic CaMKIIδ. Despite normal contractile function and Ca<sup>2+</sup> handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A (PKA) inhibition (H-89) in cardiomyocytes from the exercised db/db group abolished the differences in SR-Ca<sup>2+</sup> 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. These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type (WT).