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

Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation 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. CaMKII_C transgenic (TG) and wild-type (WT) mice performed aerobic interval exercise training over 6 wk. Cardiac function was measured by echocardiography in vivo, and cardiomyocyte shortening and intracellular Ca²⁺ handling were measured in vitro. TG mice had reduced global cardiac function, cardiomyocyte shortening (47% reduced compared with 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 reestablished Ca²⁺ homeostasis to values not different from WT. The key features to explain restored Ca²⁺ homeostasis after exercise training were increased L-type Ca²⁺ current density and flux by 79 and 85%, respectively (P < 0.01), increased sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA2a) function by 50% (P < 0.01), and reduced diastolic SR Ca²⁺ leak by 73% (P < 0.01), compared with sedentary TG mice. In 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 and improved SR Ca²⁺ handling by restoration of SERCA2a function in addition to reduced diastolic SR Ca²⁺ leak.

from Physiology via xlomafota13 on Inoreader http://ift.tt/29APbAm
via IFTTT