Exercise training reverses myocardial dysfunction induced by CaMKIIδ C overexpression by restoring Ca 2+ homeostasis

作者：Morten A. Høydal, Tomas Stølen, Sarah Kettlewell, Lars S. Maier, Joan Heller Brown, Tomas Sowa, Daniele Catalucci, Gianluigi Condorelli, Ole Johan Kemi, Godfrey L. Smith, Ulrik Wisløff · 发表于：Journal of Applied Physiology · 年份：2016 · DOI：10.1152/japplphysiol.00188.2016 · 被引用次数：19 · 研究领域：Cardiomyopathy and Myosin Studies、Cardiovascular Effects of Exercise、Cardiovascular Function and Risk Factors

Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation of cytosolic Ca(2+)/calmodulin-dependent protein kinase II (CaMKIIδC) activity. In the heart, CaMKIIδC isoform targets several proteins involved in intracellular Ca(2+) homeostasis. We hypothesized that high-intensity endurance training activates mechanisms that enable a rescue of dysfunctional cardiomyocyte Ca(2+) handling and thereby ameliorate cardiac dysfunction despite continuous and chronic elevated levels of CaMKIIδC CaMKIIδC 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 Ca(2+) handling were measured in vitro. TG mice had reduced global cardiac function, cardiomyocyte shortening (47% reduced compared with WT, P < 0.01), and impaired Ca(2+) homeostasis. Despite no change in the chronic elevated levels of CaMKIIδC, exercise improved global cardiac function, restored cardiomyocyte shortening, and reestablished Ca(2+) homeostasis to values not different from WT. The key features to explain restored Ca(2+) homeostasis after exercise training were increased L-type Ca(2+) current density and flux by 79 and 85%, respectively (P < 0.01), increased sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) function by 50% (P < 0.01), and reduced diastolic SR Ca(2+) leak by 73% (P < 0.01), compared with sedentary...