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Molecular Mechanisms in Muscular Dystrophy : a Gene Expression Profiling Study Turk, R

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Molecular Mechanisms in Muscular Dystrophy : a Gene Expression Profiling Study Turk, R Molecular mechanisms in muscular dystrophy : a gene expression profiling study Turk, R. Citation Turk, R. (2006, September 27). Molecular mechanisms in muscular dystrophy : a gene expression profiling study. Retrieved from https://hdl.handle.net/1887/4577 Version: Corrected Publisher’s Version Licence agreement concerning inclusion of doctoral License: thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/4577 Note: To cite this publication please use the final published version (if applicable). Molecular Mechanisms In Muscular Dystrophy A Gene Expression Profiling Study Molecular Mechanisms In Muscular Dystrophy A Gene Expression Profiling Study Proefschrift ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus Dr. D.D.Breimer, hoogleraar in de faculteit der Wiskunde en Natuurwetenschappen en die der Geneeskunde, volgens besluit van het College voor Promoties te verdedigen op woensdag 27 september 2006 klokke 15.00 uur door Rolf Turk Geboren te Leiden in 1975 Promotiecommissie Promotor Prof. Dr. G.J.B. van Ommen Co-promotores Dr. J.T. den Dunnen Dr. P.A.C. ‘t Hoen Referent Prof. Dr. R.M.W. Hofstra (Rijksuniversiteit Groningen) Overige leden Prof. Dr. M. Koenig (Université Louis Pasteur de Strasbourg) An experiment is a question which science poses to Nature, and a measurement is the recording of Nature’s answer. Max Planck Aan Maaike, Gerard en Annet Printed by: Drukkerij Duineveld ISBN-10: 90-9021042-3 ISBN-13: 978-90-9021042-1 Turk, Rolf Molecular mechanisms in muscular dystrophy. A gene expression profiling study. Thesis, Leiden University Medical Center September 27, 2006 © Rolf Turk No part of this thesis may be reproduced or transmitted in any form or by any means, without the written permission of the copyright owner Molecular Mechanisms In Muscular Dystrophies Preface 9 Chapter 1 Introduction 11 1. Muscle 15 1.1. Myogenesis 17 1.2. Muscle structure 19 1.3. Muscular dystrophies 26 2. Gene expression profiling 41 2.1. Introduction 41 2.2. The technique 42 3.Aim and scope of the study 46 Chapter 2 Gene expression variation between mouse inbred strains. 61 Turk R, ‘t Hoen PA, Sterrenburg E, de Menezes RX, de Meijer EJ, Boer JM, van Ommen GJ, den Dunnen JT BMC Genomics. 2004 5(1):57 Chapter 3 Muscle regeneration in dystrophin-deficient mdx mice studied by gene 71 expression profiling. Turk R, Sterrenburg E, de Meijer EJ, van Ommen GJ, den Dunnen JT, ‘t Hoen PAC BMC Genomics. 2005 6:98 Chapter 4 Common pathological mechanisms in mouse models for muscular 89 dystrophies. Turk R, Sterrenburg E, van der Wees CGC, de Meijer EJ, Groh S, Campbell KP, Noguchi S, van Ommen GJ, den Dunnen JT, ‘t Hoen PAC FASEB J. 2006 20(1):127-9 Chapter 5 Large-scale gene expression analysis of human skeletal myoblast 123 differentiation. Sterrenburg E, Turk R, ‘t Hoen PA, van Deutekom JC, Boer JM, van Ommen GJ, den Dunnen JT Neuromuscul Disord. 2004 14(8-9):507-18 Chapter 6 Intensity-based analysis of two-colour microarrays enables efficient 137 and flexible hybridization designs. ‘t Hoen PA, Turk R, Boer JM, Sterrenburg E, de Menezes RX, van Ommen GJ, den Dunnen JT Nucleic Acids Research. 2004 32(4) e41 Chapter 7 Discussion 145 1. Gene expression profiling 150 1.1. Challenges of gene expression profiling 150 1.2. Utilization of gene expression profiling 157 2. Processes in muscular dystrophy 160 2.1. Degeneration 160 2.2 Regeneration 164 2.3 Comparison between mice and men 168 3. Future leads 169 3.1. Linking gene expression to pathology 169 3.2. And vice versa 170 Chapter 8 Summary 177 Samenvatting 183 Bibliography 187 Curriculum vitae 189 Preface The muscular dystrophies are a group of neuromuscular disorders characterized by progres- sive muscle weakness and wasting. In the past two decades, the genetic causes of individual muscular dystrophies have been elucidated, which increased successful diagnosis and sub- sequent classification of the various muscular dystrophies. Although the underlying genetic defects of a large number of muscular dystrophies are now known, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di- vergence are largely unknown as well. In this thesis, gene expression profiling has been applied to study the molecular and cellular mechanisms and subsequent biological processes that play a role in muscular dystrophy. To this extent, we have determined gene expression levels in muscle tissue from different mouse models for muscular dystrophy. To characterize the processes associated with regeneration, we have compared gene expression levels in hindlimb muscle tissue of mdx and control mice in a temporal study. Additionally, we have determined the gene expression profiles of dif- ferentiating human myoblasts in vitro, since regeneration processes recapitulate myogenesis. We also set out to compare gene expression levels of different mouse models for muscular dystrophy to find common and distinct molecular mechanisms that underlie different forms of muscular dystrophy. Accordingly, we first had to determine the effects of genetic background variation between inbred mouse strains, and to study the feasibility of alternative experimental designs. The studies described above form the core of this thesis. The introduction gives an overview of myogenesis, muscle structure, muscular dystrophy, and gene expression profiling. The dis- cussion describes the experimental outcome of the studies in a broader perspective. 10 Chapter 1 Introduction 11 12 Table of Contents 1 MUSCLE 15 1.1 Myogenesis 17 1.2 Muscle Structure 19 1.2.1 Myofiber type 19 1.2.2 Muscle Precursor Cells 19 1.2.3 Extra- and Intracellular structure 20 1.2.3.1 Sarcomere 20 1.2.3.2 Costameres 22 1.2.3.3 DGC 22 1.2.3.4 The integrin-vinculin-talin system 24 1.2.3.5 Extracellular matrix 24 1.2.3.6 Transverse fixation system 25 1.3 Muscular Dystrophies 26 1.3.1 General Introduction 26 1.3.2 Dystrophinopathies 26 Clinical phenotype 27 Pathological cause and effect 27 Myofiber necrosis 27 1.3.3 Limb-Girdle Muscular Dystrophies 28 1.3.3.1 Sarcoglycanopathies 28 Clinical phenotype 29 Pathological cause and effect 29 1.3.3.2 Dysferlinopathies 29 Clinical phenotype 30 Pathological cause and effect 30 1.3.3.4 Autosomal dominant limb-girdle muscular dystrophies 30 1.3.3.5 Autosomal recessive limb-girdle muscular dystrophies 31 1.3.3.6 Congenital muscular dystrophy 31 1.3.4 Animal models for muscular dystrophy 31 1.3.4.1 Mouse models for dystrophinopathy 32 Alternative mouse models for dystrophinopathy 33 Utrophin-deficient mice 33 1.3.4.2 Mouse models for sarcoglycanopathy 33 α-Sarcoglycan deficient mice 34 β-Sarcoglycan deficient mice 34 γ-Sarcoglycan deficient mice 35 δ-Sarcoglycan deficient mice 35 1.3.4.3 Mouse models for dysferlinopathy 36 1.3.4.4 Other animal models for muscular dystrophy 36 Canine models for muscular dystrophy 36 Feline models for muscular dystrophy 36 Rodent models for muscular dystrophy 37 1.3.5 Secondary pathological processes 37 1.3.5.1 Necrosis / Apoptosis 37 1.3.5.2 Inflammation 38 1.3.5.3 Regeneration 39 13 2 GENE EXPRESSION PROFILING 41 2.1 Introduction 41 2.2 The technique 42 2.2.1 Target handling 42 2.2.2 Platforms 42 2.2.2.1 cDNA microarrays 44 2.2.2.2 Spotted oligonucleotide microarrays 44 2.2.2.3 In situ lithographic microarrays 44 2.2.3 Applications 45 3 AIM AND SCOPE OF THE STUDY 46 Aim of the study 46 4 REFERENCES 49 14 Introduction Muscle 1 Muscle According to the Oxford dictionary, muscle is an elastic substance in the body that can be tightened or loosened to produce movement. More specifically, muscle tissue has the ability to contract and relax in order to produce motion. Muscle comes in three forms, namely skeletal, cardiac, and smooth muscle. The research in this thesis will mainly focus on skeletal muscle tissue. The function of skeletal muscle tissue concerns the ability to contract and extend in or- der to position bones or skin. This function is accomplished by the building blocks of muscle, the myofibers. Myofibers are long, cylindrical, multinucleated cells that are packed with con- tractable filaments. These filaments, or myofibrils, are primarily made of thin actin and thick myosin molecules, which are aligned precisely. Successively ordered contractile units, or sar- comeres, result in the banded, or striated, appearance of skeletal muscle tissue. Each myofiber is wrapped in a sheet of connective tissue, also known as the endomysium. A bundle of myofibers forms a fascicle, which is surrounded by the perimysium. Finally, an individual muscle consists of multiple fascicles, is surrounded by the epimysium, and is con- nected to skeletal or skin-like structures via tendons (Figure 1). Thus, the anatomy of muscle tissue reflects an highly organized structure. Muscle tissue does not consist of myofibers alone. Muscle action is controlled by the stimula- tion of a motor neuron via the neuromuscular junction. The axonal ending of the motor neuron transfers an action potential, which results in the contraction of the myofiber. Each myofiber is activated via a single neuromuscular junction. Furthermore, muscle tissue is perfused by the vascular system, which is responsible for both the delivery of oxygen and nutrients, and the disposal of metabolic waste. Within the muscle tissue, the internal innate defense is pres- ent, which helps to protect the muscle from pathogens, and helps tissue repair processes. The effector cells of the innate defense system are mainly represented by macrophages, dendritic cells, and B-cells148.
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