TY - JOUR
T1 - Exercise training reverses myocardial dysfunction induced by CaMKIIC overexpression by restoring Ca2+ homeostasis
AU - Høydal, Morten A.
AU - Stølen, Tomas O.
AU - Kettlewell, Sarah
AU - Maier, Lars S.
AU - Brown, Joan Heller
AU - Sowa, Tomas
AU - Catalucci, Daniele
AU - Condorelli, Gianluigi
AU - Kemi, Ole J.
AU - Smith, Godfrey L.
AU - Wisløff, Ulrik
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation of cytosolic Ca2/calmodulin-dependent protein kinase II (CaMKIIC) activity. In the heart, CaMKIIC 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 CaMKIIC. CaMKIIC 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 CaMKIIC, 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 CaMKIIC 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.
AB - Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation of cytosolic Ca2/calmodulin-dependent protein kinase II (CaMKIIC) activity. In the heart, CaMKIIC 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 CaMKIIC. CaMKIIC 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 CaMKIIC, 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 CaMKIIC 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.
KW - Calcium handling
KW - CaM kinase
KW - Exercise training
KW - Heart disease
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U2 - 10.1152/japplphysiol.00188.2016
DO - 10.1152/japplphysiol.00188.2016
M3 - Article
AN - SCOPUS:84983778254
VL - 121
SP - 212
EP - 220
JO - Journal of Applied Physiology
JF - Journal of Applied Physiology
SN - 8750-7587
IS - 1
ER -