title: Exercise training reverses myocardial dysfunction induced by CaMKIIδC overexpression by restoring Ca2+ homeostasis.
abstract: 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 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 CaMKIIδC mice are mediated via increased L-type Ca(2+) channel currents and improved SR Ca(2+) handling by restoration of SERCA2a function in addition to reduced diastolic SR Ca(2+) leak.
authors.affiliation: Norwegian University of Science and Technology, K. G. Jebsen Centre of Exercise in Medicine, Trondheim, Norway; morten.hoydal@ntnu.no.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Høydal
authors.affiliation: Norwegian University of Science and Technology, K. G. Jebsen Centre of Exercise in Medicine, Trondheim, Norway;
authors.forename: Tomas O
authors.initials: TO
authors.lastname: Stølen
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Sarah
authors.initials: S
authors.lastname: Kettlewell
authors.affiliation: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany;
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: University of California, San Diego, La Jolla, California;
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.affiliation: Heart Center of the University of Göttingen, Göttingen, Germany; and.
authors.forename: Tomas
authors.initials: T
authors.lastname: Sowa
authors.affiliation: National Research Council, Institute of Genetic and Biomedical Research-UOS Milan and Humanitas Research Hospital, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.affiliation: National Research Council, Institute of Genetic and Biomedical Research-UOS Milan and Humanitas Research Hospital, Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Ole J
authors.initials: OJ
authors.lastname: Kemi
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: Norwegian University of Science and Technology, K. G. Jebsen Centre of Exercise in Medicine, Trondheim, Norway;
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisløff
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology*; D004452:Echocardiography / Q000379:methods; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: CaM kinase; calcium handling; exercise training; heart disease