Exercise training reverses myocardial dysfunction induced by CaMKII{delta}C overexpression by restoring Ca2+-homeostasis

Aim: Several conditions of heart disease, including heart failure and diabetic cardiomyopathy are associated with up-regulation of cytosolic Ca²⁺/calmodulin-dependent protein kinase II (CaMKII_C) activity. In the heart, CaMKII_C isoform targets several proteins involved in intracellular Ca²⁺ homeostasis. We hypothesized that high intensity endurance training activates mechanisms that enable a rescue of dysfunctional cardiomyocyte Ca²⁺ handling and thereby ameliorate cardiac dysfunction despite continuous and chronic elevated levels of CaMKII_C. Methods: CaMKII_C transgenic (TG) and wild-type (WT) mice performed aerobic interval exercise training over 6 weeks. Cardiac function was measured by echocardiography in vivo, and cardiomyocyte shortening and intracellular Ca²⁺-handling in vitro. Results: TG mice had reduced global cardiac function, cardiomyocyte shortening (47% reduced compared to WT, P<0.01) and impaired Ca²⁺-homeostasis. Despite no change in the chronic elevated levels of CaMKII_C, exercise improved global cardiac function, restored cardiomyocyte shortening, and re-established Ca²⁺-homeostasis to values not different from WT. The key features to explain restored Ca²⁺-homeostasis after exercise training were increased I_CaL density and flux by 79% and 85%, respectively (P<0.01), increased SERCa2a function by 50% (p<0.01) and reduced diastolic SR Ca²⁺-leak by 73% (P<0.01), compared to sedentary TG mice. Conclusion: Exercise training improves global cardiac function as well as cardiomyocyte function in the presence of a maintained high CaMKII activity. The main mechanisms of exercise-induced improvements in TG CaMKII_C mice are mediated via increased L-type Ca²⁺ channel currents, improved SR Ca²⁺-handling by restoration of SERCA2a function in addition to reduced diastolic SR Ca²⁺-leak.

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