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To Phosphorylate Or Not to Phosphorylate: the Role of Tropomyosin Phosphorylation in Cardiac Function and Disease

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To Phosphorylate Or Not to Phosphorylate: the Role of Tropomyosin Phosphorylation in Cardiac Function and Disease TO PHOSPHORYLATE OR NOT TO PHOSPHORYLATE: THE ROLE OF TROPOMYOSIN PHOSPHORYLATION IN CARDIAC FUNCTION AND DISEASE A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) In the Department of Molecular Genetics, Biochemistry and Microbiology of the College of Medicine 2012 By Emily M. Schulz B.S. Ohio University, 2004 Committee Chair: David F. Wieczorek, Ph.D. 1 ABSTRACT Tropomyosin (Tm) is an α-helical coiled-coil protein crucial in the calcium dependent regulation of the thin filament of the sarcomere. α-Tm is phosphorylated solely at serine 283 and phosphorylation levels are tightly regulated. Approximately 70% of total cardiac Tm phosphorylated during fetal development, decreasing to 30% during adulthood. Total Tm phosphorylation is altered in multiple mouse models of cardiac disease, including hypertrophic cardiomyopathy, dilated cardiomyopathy and myocardial infarction, indicating that Tm phosphorylation may play a role in the initiation, progression or modulation of cardiac disease. To determine the effect of loss of α-Tm phosphorylation, a transgenic (TG) mouse model was generated in which cardiac specific α-Tm expresses an alanine at amino acid 283 rather than a serine (α-Tm S283A). Counter to previous studies on Tm phosphorylation performed in vitro, at basal levels, significantly decreased α-Tm phosphorylation has no effect. TG animals exhibit normal cardiac function, efficient contractility and relaxation under basal conditions and under β-adrenergic stimulation. However, when α-Tm S283A TG animals are subjected to transaortic constriction (TAC), the TG TAC operated animals fail more quickly than the non-transgenic (NTG) TAC operated littermates. Interestingly, in TG hearts, there is an increase in SERCA2a expression and an increase in PLN phosphorylation at Ser16. This increase in energetic demand placed on the heart both by the increase in SERCA2a activity coupled with the increased energetic demand that occurs during the onset of cardiac disease may be the basis of the more rapid cardiac failure in the TG TAC mice. After examining the effect of decreased α-Tm phosphorylation in the context of an acute, extrinsic cardiac stressor, a model of decreased α-Tm phosphorylation was made in the context of a chronic, intrinsic stressor. These α-Tm 180-S283A double mutant TG (DMTG) animals were surprising in that the α-Tm 180 familial hypertrophic cardiomyopathy phenotype was completely rescued in a TG line that exhibited Tm phosphorylation levels similar those seen in the α-Tm S283A TG hearts. This rescue occurred at iii morphological and physiological levels, including echocardiographic analysis. In addition, examination 2+ of detergent extracted skinned fiber bundles indicate that Ca sensitivity and cooperativity (nH) is rescued to NTG levels, indicating that the rescue occurs primarily at the level of the sarcomere. The DMTG mutant hearts show a significant decrease in PLN phosphorylation at both Ser16 and Thr17 compared to NTG and α-Tm S283A TG hearts. However, DMTG levels of PLN phosphorylation at both sites are significantly increased compared to α-Tm 180 levels, which may possibly account for the hypercontractile phenotype seen in the DMTG mice when evaluated via echocardiography. These data seem to indicate that dephosphorylating Tm in the context of hypertrophy might be of benefit to the overall function of the heart. However, it is important to examine the effect of increased Tm phosphorylation in the context of other cardiac disease, such as dilated cardiomyopathy or myocardial infarction. The studies presented here, in addition to the proposed studies, would possibly increase understanding of the functional consequences of Tm phosphorylation which may lead to possible therapeutic interventions. iv v DEDICATION This work is dedicated to Brant Schulz. Husband, cheerleader, voice of reason, support system, chef and cat-wrangler. I couldn’t have done this without you. vi NANOS GIGANTUM HUMERIS INSIDENTES My deep thanks and gratitude go to Dr. David F. Wieczorek. The continuous support and encouragement he offered has been crucial to any small contributions I have made to our field. I especially thank him for teaching me to think independently, creatively and critically. I also extend my thanks to the members of my committee. Dr. Andrew Herr, Dr. James Lessard, Dr. Jeffery Molkentin and Dr. Gary Shull have supported me and significantly contributed to my understanding of how to do great science. I thank members of my lab: Dr. Ganapathy Jagatheesan and Dr. Sudarsan Rajan for helping me to understand what type of scientist I wanted to become. Hannah Yaejee Hong generated the construct for the α-Tm 180-S283A studied in this dissertation. Shelby Moore generated the companion construct, α- Tm 180-S283D. My deep thanks go to Dr. Vikram Prasad and Dr. Tracy Pritchard for their technical support, vast store of knowledge they never hesitated to share and their interest in the research of a graduate student from a neighboring lab. Maureen Bender has been crucial to the work I have done in this lab. I am lucky to have many good friends who have supported me throughout this process. We are spread out through the country and the world but their support and love has been very important to me. Although equally all are dear to me, Dr. Susan Vidovichenko, Dr. Emily Bradford, Dr. Naomi Oshiro, Dr. Palanikumar Manoharan, Kanimozhi Vairamani, Robyn Pilcher-Roberts, Cat Tucker and Lana Goodrich deserve special mention here. Thank you. This work would not have been possible without the financial support of TG T36-HL07382 to Dr. A. Schwartz. Finally, I must express my deepest thanks and gratitude to my family. My parents, Russell and Robin Thompson, my sisters, my extended family and my family by marriage have done so much to support me in my endeavors. Stress relief and puffy support was provided by Nimbus, Olliver, Gilbert and Jayne. Without the love and support of my husband, Brant Schulz, this work would not have been possible. vii TABLE OF CONTENTS ABSTRACT ................................................................................................................................................ iii DEDICATION............................................................................................................................................. v NANOS GIGANTUM HUMERIS INSIDENTES ................................................................................. vii TABLE OF CONTENTS ........................................................................................................................ viii LIST OF FIGURES ................................................................................................................................... xi LIST OF TABLES ................................................................................................................................... xiii LIST OF ABBREVIATIONS ................................................................................................................. xiv CHAPTER 1: INTRODUCTION .............................................................................................................. 1 Tropomyosin ............................................................................................................................................. 1 Tropomyosin Genes .................................................................................................................................. 1 Tropomyosin Protein ................................................................................................................................ 3 Striated Muscle Tropomyosins ................................................................................................................. 6 Tropomyosin in Muscle Contraction ........................................................................................................ 9 Ca2+ Flux Proteins ................................................................................................................................... 12 Exercise Training and Physiological Hypertrophy ................................................................................. 16 Phosphorylation of Myofibrillar Proteins ............................................................................................... 17 Phosphorylation of Tropomyosin ........................................................................................................... 21 Cardiac Hypertrophy and Tropomyosin ................................................................................................. 22 The Goal of this Dissertation .................................................................................................................. 27 CHAPTER 2: MATERIALS AND METHODS .................................................................................... 29 Generation of α-Tm S283A and α-Tm 180-S283A TG Mice ................................................................. 29 Genotyping of TG Mice .......................................................................................................................... 30 Northern Blot Analyses ........................................................................................................................... 30 Real Time RT-PCR Analysis .................................................................................................................
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