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A Novel Role for Glycogenin in the Regulation of Glycogen Metabolism

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A Novel Role for Glycogenin in the Regulation of Glycogen Metabolism A Novel role for glycogenin in the regulation of glycogen metabolism Giorgia Testoni ADVERTIMENT . La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX ( www.tdx.cat ) i a través del Dipòsit Digital de la UB ( diposit.ub.edu ) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposici ó des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB . No s’autori tza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA . La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR ( www.tdx.cat ) y a través del Repositorio Di gital de la UB ( diposit.ub.edu ) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB . No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING . On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX ( www.tdx.cat ) service and by the UB Digital Repository ( diposit.ub.edu ) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized n or its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository . Introducing its content in a window or frame foreign to th e TDX service or to the UB Digital Repository is not authorized (framing). Tho s e rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the au thor. A NOVEL ROLE FOR GLYCOGENIN IN THE REGULATION OF GLYCOGEN METABOLISM Memoria presentada por GIORGIA TESTONI Para optar al grado de Doctora por la Universidad de Barcelona Tesis realizada en el Institut de Recerca Biomèdica (IRB Barcelona), Laboratorio de Ingeniería metabólica y terapia de la diabetes Tesis adscrita al programa de doctorado en Biomedicina Universidad de Barcelona El Director de la tesis La autora Joan J. Guinovart Cirera Giorgia Testoni Noviembre, 2015 A NOVEL ROLE FOR GLYCOGENIN IN THE REGULATION OF GLYCOGEN METABOLISM GIORGIA TESTONI Fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) At Institute for Research in Biomedicine (IRB Barcelona), Metabolic Engineering and Diabetes Laboratory Doctoral program in Biomedicine University of Barcelona Thesis director Author Joan J. Guinovart Cirera Giorgia Testoni November 2015 Table of Contents Abbreviations .................................................................................................................. 9 Introduction ........................................................................................................... 13 Glycogen .............................................................................................................................. 13 Glycogen metabolism .......................................................................................................... 14 The need for a primer in the glycogen initiation ................................................................ 17 Glycogenin ........................................................................................................................... 18 Glycogen Synthase .............................................................................................................. 21 Skeletal muscle .............................................................................................................. 22 Skeletal muscle metabolism ................................................................................................ 23 Fiber switch ......................................................................................................................... 27 Glycogen in skeletal muscle ............................................................................................ 29 Mechanism of glycogen synthase control by exercise ...................................................... 29 Glycogen storage diseases (GSDs) ................................................................................... 30 Objectives .............................................................................................................. 35 Results ................................................................................................................... 37 1. Generation of the Gyg KO animal model ..................................................................... 37 1.1 Introduction ................................................................................................................... 37 1.2 Generation of the animal model and survival analysis ................................................. 37 1.3 Morphology at different embryonic stages and causes of death ................................. 38 1.4 Conclusions .................................................................................................................... 43 2. Gyg KO embryos accumulate glycogen ........................................................................ 45 2.1 Detection of glycogen in Gyg KO embryos .................................................................... 45 2.2 Generation of Gyg Del animal model ............................................................................ 47 3. Characterization of adult Gyg KO animals ................................................................... 51 3.1 Glycogenin depletion does not impair weight and size of the mice ............................. 51 3.2 Glycogenin mRNA and protein detection ..................................................................... 51 3.3 Glycogen measurement in surviving Gyg KO mice ........................................................ 53 3.4 Conclusions .................................................................................................................... 56 4. Characterization of glycogen synthesized in absence of glycogenin .............................. 59 4.1 Introduction ................................................................................................................... 59 4.2 Analysis of Gyg KO glycogen .......................................................................................... 59 4.3 Aged Gyg KO animals present lower levels of Corpora Amylacea ................................ 67 4.4 Conclusions .................................................................................................................... 69 5. Search of a putative substitute protein for glycogen priming ....................................... 71 5.1 Introduction ................................................................................................................... 71 5.2 Determination of glycogenin peptide profile ................................................................ 71 5.3 Purification of glycogen from liver ................................................................................ 72 5.4 Purification of glycogen from muscle ............................................................................ 74 5.5 Conclusions .................................................................................................................... 76 6. Changes in glycogen metabolism ................................................................................ 77 6.1 Introduction ................................................................................................................... 77 6.2 Glycogen metabolism in heart and skeletal muscle ...................................................... 77 6.3 Glycogen metabolism in liver ........................................................................................ 82 6.4 Glycogen metabolism in primary hepatocytes ............................................................. 86 6.5 Conclusions .................................................................................................................... 88 7. Physiological characterization of Gyg KO mice ............................................................. 89 7.1 Glycemic response to metabolic stimuli ....................................................................... 89 7.2 Muscle response to physical exercise ........................................................................... 91 7.3 Energy expenditure and calorimetric parameters ........................................................ 98 7.4 Conclusions .................................................................................................................
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