title: Long-term simulated microgravity causes cardiac RyR2 phosphorylation and arrhythmias in mice.
abstract: BACKGROUND
  Long-term exposure to microgravity during space flight may lead to cardiac remodeling and rhythm disturbances. In mice, hindlimb unloading (HU) mimics the effects of microgravity and stimulates physiological adaptations, including cardiovascular deconditioning. Recent studies have demonstrated an important role played by changes in intracellular Ca handling in the pathogenesis of heart failure and arrhythmia. In this study, we tested the hypothesis that cardiac remodeling following HU in mice involves abnormal intracellular Ca regulation through the cardiac ryanodine receptor (RyR2).
  
  
  RESULTS
  Mice were subjected to HU by tail suspension for 28 to 56 days in order to induce cardiac remodeling (n=15). Control mice (n=19) were treated equally, with the exception of tail suspension. Echocardiography revealed cardiac enlargement and depressed contractility starting at 28 days post-HU versus control. Moreover, mice were more susceptible to pacing-induced ventricular arrhythmias after HU. Ventricular myocytes isolated from HU mice exhibited an increased frequency of spontaneous sarcoplasmic reticulum (SR) Ca release events and enhanced SR Ca leak via RyR2. Western blotting revealed increased RyR2 phosphorylation at S2814, and increased CaMKII auto-phosphorylation at T287, suggesting that CaMKII activation of RyR2 might underlie enhanced SR Ca release in HU mice.
  
  
  CONCLUSIONS
  These data suggest that abnormal intracellular Ca handling, likely due to increased CaMKII phosphorylation of RyR2, plays a role in cardiac remodeling following simulated microgravity in mice.
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Pavel M
authors.initials: PM
authors.lastname: Gershovich
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Reynolds
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States; Center for Space Medicine/National Space Biomedical Research Institute, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Sutton
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States; Department of Pediatrics/Cardiology, Texas Children's Hospital, Houston, TX, United States.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Miyake
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States; Department of Medicine/Cardiology, Baylor College of Medicine, Houston, TX, United States; Center for Space Medicine/National Space Biomedical Research Institute, Baylor College of Medicine, Houston, TX, United States. Electronic address: wehrens@bcm.edu.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D019417:Hindlimb Suspension; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D020257:Ventricular Remodeling / Q000502:physiology; D018474:Weightlessness Simulation / Q000009:adverse effects*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Arrhythmia; Ca/calmodulin-dependent kinase II; Calcium; Microgravity; Ryanodine receptor