title: Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy.
abstract: Cardiac myocyte-specific deletion of either glycogen synthase kinase (GSK)-3α and GSK-3β leads to cardiac protection after myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration because of the fact that all GSK-3-targeted drugs, including the drugs already in clinical trial target both isoforms of GSK-3, and none are isoform specific.
  
  
  
  To identify the consequences of combined deletion of cardiac myocyte GSK-3α and GSK-3β in heart function.
  
  
  
  We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, double-knockout hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from double-knockout implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. Double-knockout cardiac myocytes showed cell cycle progression resulting in increased DNA content and multinucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe-induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes.
  
  
  
  Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis, and its loss is incompatible with life because of cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy.
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Firdos
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Shan
authors.initials: S
authors.lastname: Parikh
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Nichole E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Vipin K
authors.initials: VK
authors.lastname: Verma
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Ancai
authors.initials: A
authors.lastname: Yuan
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Santhanam
authors.initials: S
authors.lastname: Shanmughapriya
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Walter
authors.initials: W
authors.lastname: Koch
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.).
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.). thomas.l.force@vanderbilt.edu hind.lal@vanderbilt.edu.
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.affiliation: From the Division of Cardiovascular Medicine (F.A., V.K.V., Y.G., H.L., T.F.) and Department of Pharmacology (S.P., Y.G.), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (J.Z., N.E.H., S.R., J.S., A.Y., S.S., E.G., W.K., M.M., R.K.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.R.W.). thomas.l.force@vanderbilt.edu hind.lal@vanderbilt.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: GSK-3; cell cycle; dilated cardiomyopathy; heart failure; mitotic catastrophe