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The Role of USP19 Deubiquitinating Enzyme in Muscle Differentiation in Vitro

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The Role of USP19 Deubiquitinating Enzyme in Muscle Differentiation in Vitro The role of USP19 deubiquitinating enzyme in muscle differentiation in vitro By Miao Miao Faculty of Medicine Department Biochemistry McGill University, Montreal, Quebec, Canada December 2010 A thesis submitted to McGill University in partial fulfillment of the requirement for the degree of Master of Science @Miao Miao 2010 0 TABLE OF CONTENTS ............................................................................................ 1 ACKNOWLEDGEMENTS ........................................................................................ 4 ABSTRACT ........................................................................................................ 6 RÉSUMÉ .......................................................................................................... 8 LIST OF ABBREVIATIONS ..................................................................................... 10 I. INTRODUCTION 1 Muscle wasting 1.1 Muscle wasting in disease ………………………………………………….. 11 1.2 Different proteolytic systems in muscle wasting …………..……… 14 1.3 Ubiquitin proteasome system and ubiquitin signalling …..……. 16 1.4 Control of ubiquitination in muscle wasting ……………………..… 19 2 DUBs 2.1 Mechanism of DUBs …………………………………………………………… 21 2.2 Structure of DUBs ……………………………………………………………… 22 2.3 Functions of DUBs …………………………………….………………………. 23 2.4 Regulations of DUBs ………………………………………………………….. 26 3 Function of USP19 deubiquitinating enzyme 3.1 Function of USP19 in muscle wasting …………………………………. 27 3.2 Function of USP19 in muscle differentiation ……………………..… 29 3.3 Objectives of this thesis ……………………………………………………… 33 1 II. MATERIALS AND METHODS 2.1 Cell culture and transfection .....................................……………….. 34 2.2 Northern blotting …………………………………………………………………….. 35 2.3 Western blotting ........................................................................ 36 2.4 Adenovirus generation, infection and fusion index determination ………………………………………………………………….. 37 2.5 Cell fractionation ………………………………………………………………………. 38 III. RESULTS 3.1 Depletion of USP19 increases mRNA levels of MHC and tropomyosin …………………………………………………..……….. 39 3.2 USP19 regulates the expression of the myogenic regulatory factor myogenin ………………………………………………………………..……. 41 3.3 Re-expressing USP19 in myotubes treated with USP19 siRNA reverses the increases in myogenin and myosin heavy chain (MHC) ………………………………………………………. 43 2 3.4 Overexpression of USP19 decreases myogenin and major myofibrillar proteins ……………………………………………………………….. 45 3.5 USP19 inhibits fusion of L6 myoblasts ………………………………….…… 47 3.6 USP19 mRNA and protein expression is regulated during muscle differentiation in L6 …………………………………..……… 51 3.7 Localization of USP19 during muscle cell differentiation ………..…. 54 IV. DISCUSSION ........................................................................................ 56 V. REFERENCES ........................................................................................ 61 3 ACKNOWLEDGEMENTS I would like to thank the individuals who have helped me in completing my master’s degree. First and foremost, I would like to thank my supervisor Dr. Simon Wing. He is an amazing teacher who encourages active intellectual pursuit through a series of questions that lead to great interest and understanding of the foundations of scientific research. He has influenced me to a great extent in terms of my growth both as a scientist and a person. Through his guidance, I have developed independent learning and critical thinking skills both of which are very important for a future career in health care. I am grateful to his guidance and support in developing my professional and personal skills. He is someone that I will continue to respect for years to come. I would like to thank Nathalie Bedard for her invaluable support in technical skills and Yaoming Yang for good advice in experimental procedures. I also would like to thank Marie Plourde, for her friendly smiles. To my fellow colleagues Priyanka Sundaram, Yu Lu, Tamara Moore, Xue Feng, I thank you for our many happy conversations. It was truly an enriching experience to have worked with so many interesting and kind people. I would like to thank my Research Academic Committee members Dr. Kenneth Hastings and Professor Imed Gallouzi for their time, advice, and guidance in my project. 4 Finally, I would like to thank my parents for their continuous support and encouragement during both the happy and difficult times in my academic life. 5 ABSTRACT Muscle wasting is a significant complication of many diseases. Previous work has shown that USP19 mRNA expression is increased in muscle undergoing atrophy in rodents [1]. To further explore the role of USP19 in muscle, siRNA-mediated silencing was used in L6 muscle cells. Depletion of USP19 resulted in increased major myofibrillar protein levels [2]. These effects of silencing USP19 on myofibrillar protein expression may be due to the effects of USP19 on the differentiation of muscle cells. Therefore, in this thesis I further characterized the mechanism by which depletion of USP19 enhances expression of myofibrillar proteins. MHC and tropomyosin mRNA levels were increased upon USP19 silencing, suggesting that the observed increases in protein levels were due to increased transcription. Myogenin, a transcription factor in the myogenic regulatory factor family that regulates muscle differentiation, was increased by more than two fold at both mRNA and protein levels when USP19 was silenced and found to be responsible for mediating the increase in myofibrillar protein expression. The negative role of USP19 in muscle differentiation was confirmed as overexpressing USP19 resulted in decreased myogenin and major myofibrillar protein expression at the molecular level and decreased myotube fusion at the morphological level. The regulation of USP19 itself during muscle differentiation was then investigated. The mRNA levels were found to increase by ~ 4 fold from day 0 to day 5 of differentiation, while there was a ~ 1.5 fold increase in protein 6 levels. USP19 is localized in both the cytosol and the nucleus but there was increased localization in the nucleus on day 4 of muscle cell differentiationd. In conclusion, USP19 negatively regulates muscle differentiation. Since new myoblast fusion and myofiber formation may occur during recovery from wasting, an inhibitor to USP19 could be a new approach to the treatment of muscle wasting. 7 RÉSUMÉ L’atrophie musculaire est une complication considérable de plusieurs maladies. Des études antérieures ont démontré que l’expression de l’ARN messager de USP19 est régulé à la hausse dans plusieurs modèles d’atrophie musculaire chez les rongeurs [1]. Afin de mieux comprendre le rôle de USP19 dans les muscles, nous avons utilisé des ARN interférents dans des cellules musculaires L6. La réduction des niveaux de USP19 a conduit à une augmentation des niveaux des protéines myofibrillaires prédominantes *2+. Les conséquences d’une réduction des niveaux de USP19 sur l’expression des protéines myofibrillaires pourrait être dû à l’effet de USP19 sur la différentiation des cellules musculaires. Par conséquent, dans cette thèse, j’ai caractérisé plus en profondeur le mécanisme par lequel une réduction de USP19 mène à une augmentation de l’expression de protéines myofibrillaires. Nous avons observé que les niveaux d’ARN messagers de MHC et de la tropomyosine sont augmenté suite à la réduction de USP19 par ARN interférent, ce qui suggère que la hausse des niveaux protéiques est dû à une augmentation de la transcription. Le facteur de transcription myogénine fait partie de la famille des facteurs de régulation myogénique impliqués dans la différentiation musculaire et est responsable de l’augmentation de l’expression des protéines myofibrillaires. Nous avons observé que le niveau de ces protéines sont augmentés de plus de deux fois autant au niveau de l’ARN messager qu’au niveau protéique quand USP19 est réduit par ARN interférent. Le rôle de USP19 8 dans la différentiation musculaire a aussi été démontré en surexprimant USP19 dans des cellules musculaires. Une augmentation des niveaux de USP19 a conduit à une réduction de l’expression des principales protéines myofibrillaires ainsi que la myogénine au niveau moléculaire et à une réduction de la différentiation des myotubes au niveau morphologique. La regulation de USP19 pendant la différentiation musculaire a donc été étudié. Les niveaux d’ARN messagers de USP19 sont augmentés 4 fois durant les 5 premiers jours de différentiation alors que les niveaux protéiques sont augmentés 1.5 fois. De plus, USP19 est localisé autant dans la partie cytosolique que dans le noyau cellulaire. Une augmentation de la localisation de USP19 dans le noyau au 4ème jour de différentiation a été observé. En conclusion, USP19 est un régulateur négatif de la différentiation musculaire. Puisque la formation de nouveau fibres musculaires peut apparaître suite à la récupération de l’atrophie, un inhibiteur de USP19 pourrait être une approche intéressante pour le traitement de l’atrophie musculaire. 9 LIST OF ABBREVIATIONS #7 , #43: USP19 specific siRNA oligonucleotides CTL: Control DUB: Deubiquitinating enzyme E1: Ubiquitin activating enzyme E2: Ubiquitin conjugating enzyme E3: Ubiquitin protein ligase EDL: Extensor digitorum longus MAFbx/Atrogin-1: Muscle Atrophy F-box/ Atrogin-1 MURF: Muscle-specific Ring Finger MHC: Myosin Heavy Chain MRF: Myogenic Regulatory Factor UPS: Ubiquitin Proteasome System 10 I. INTRODUCTION Skeletal muscle accounts for approximately half of body
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