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Sumoylation Is a Post-Translational Modification Regulating Skeletal Muscle Pathophysiology

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Sumoylation Is a Post-Translational Modification Regulating Skeletal Muscle Pathophysiology From the Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden SUMOylation is a post-translational modification regulating skeletal muscle pathophysiology Gabriel Antonio Heras Arribas Stockholm 2020 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by US-AB universitetsservice Cover: Mitochondrial distribution of GFP-tagged MuRF1 in murine myoblasts (C2C12) © Gabriel Antonio Heras Arribas, 2020 ISBN 978-91-7831-886-5 SUMOylation is a post-translational modification regulating skeletal muscle pathophysiology THESIS FOR DOCTORAL DEGREE (Ph.D.) By Gabriel Antonio Heras Arribas Principal Supervisor: Opponent: Associate Professor Stefano Gastaldello, PhD Assoc. Prof. Dorianna Sandoná Karolinska Institutet, Sweden Padova University, Italy Department of Physiology and Pharmacology Department of Biomedical Sciences Division of Pathophysiology of Striated Muscles Co-supervisor(s): Assistant professor Simone Codeluppi, PhD Examination Board: Karolinska Institutet, Sweden Prof. Nico Dantuma Department of Medical Biochemistry and Karolinska Institutet, Sweden Biophysics Department of Biomedical Sciences Dr. Nicola Cacciani Prof. Claes Andréasson Karolinska Institutet, Sweden Stockholm University, Sweden Department of Physiology and Pharmacology Department of Molecular Biosciences Division of Molecular Cell Biology Professor Lars Larsson Karolinska Institutet, Sweden Assoc. Prof. Johanna Lanner Department of Physiology and Pharmacology Karolinska Institutet, Sweden Department of Physiology and Pharmacology Division of Molecular Muscle Physiology and Pathophysiology To my wife Esther, thank you for pushing me to reach for the stars. To my parents Maria Pilar Arribas and Jose Antonio Heras, for being there every step of the way. “Do. Or do not. There is no try”. ABSTRACT The research of this thesis is focused to investigate the role of SUMOylation, a protein post-translational modification reaction, implemented to the skeletal muscle pathophysiology area. SUMOylation is regulated by an enzymatic cascade of coordinated events capable of the reversible attachment of the Small Ubiquitin-like Modifier (SUMO) on to the targeted proteins. This reaction is highly susceptible to intra- or extracellular stimuli and responds immediately by altering the expression of its enzymes and the final SUMOylated products as an adaptation to the new status. Skeletal muscle is a complex organ and it is unfortunately affected by severe diseases, which represent widespread pathologies affecting millions of people every year. Until now, despite many studies performed on the field, there is still a lack of information about the cellular and molecular mechanisms predicting or describing the early events of human muscle pathologies. We investigated different processes occurring among the SUMO network and the skeletal muscle functions and related them to the normal muscle activities or muscle alterations, from rodent models of muscle pathologies to human muscle biopsies. We described a tight correlation between the abundance of SUMO conjugated proteins and the different skeletal muscle fiber types. This association was quickly altered as a consequence of muscle activity changes or early events in acquired muscular disorders. We provided also a new skeletal muscle embryological classification based exclusively on the diverse abundances and distribution of the SUMO enzymes. A combination of innovative techniques allowed us to identify and validate new SUMO skeletal muscle targets and determine the modulation of the SUMO enzymes abundances during myogenesis and the progression of acquired muscle diseases. These results assigned to some SUMO components a potential biomarker function to predict skeletal muscle dysfunctions. Thus, the investigation on skeletal muscle disuse allowed us to discover a new transcriptional regulation mechanism of the E2 SUMO enzyme, Ubc9, mediated by the transcriptor factor PAX6 in soleus muscles under unloaded conditions. Finally, we proved that targeting the SUMO pathway using chemical drugs as BGP- 15 or anacardic acid have a positive effect on the treatment of myopathies and improving myogenesis under hyperglycemic conditions. 7 8 LIST OF SCIENTIFIC PAPERS I. A Proteomic Approach to Identify Alterations in the Small Ubiquitin-like Modifier (SUMO) Network during Controlled Mechanical Ventilation in Rat Diaphragm Muscle. Namuduri AV, Heras G, Mi J, Cacciani N, Hörnaeus K, Konzer A, Lind SB, Larsson L, Gastaldello S.Mol Cell Proteomics. 2017 June 16. II. Muscle RING-finger protein-1 (MuRF1) functions and cellular localization are regulated by SUMO1 post-translational modification. Heras G*, Namuduri AV*, Traini L, Shevchenko G, Falk A, Bergström Lind S, Mi J, Tian G, Gastaldello S. J Mol Cell Biol. 2018 June 4. (*Contributed equally to this study) III. Expression of SUMO enzymes is fiber type dependent in skeletal muscles and is dysregulated in muscle disuse. Namuduri AV, Heras G, Lauschke MV, Maurizio Vitadello, Traini L, Cacciani N, Gorza L, Gastaldello S. FASEB J. 2019 December 16 IV. High glucose-induced oxidative stress accelerates C2C12 myogenesis by altering SUMO reactions. Liu X*, Heras G*, Lauschke MV, Mi J, Geng T, Gastaldello S. Manuscript (*Contributed equally to this study) Additional publications (not included in the thesis) “Circadian regulation of phosphodiesterase 6 genes in zebrafish differs between cones and rods: Implications for photopic and scotopic vision”. Abalo XM, Lagman D, Heras G, del Pozo A, Eggerta J, Larhammar D. Vision Research. 2019 December 16. 9 10 CONTENTS INTRODUCTION ................................................................................................................ 17 1. MUSCLE ....................................................................................................................... 17 1.1. Skeletal muscle .................................................................................................... 18 1.1.1. Myosin ..................................................................................................... 20 1.1.2. Actin ........................................................................................................ 20 1.1.3. Troponin .................................................................................................. 20 1.1.4. Tropomyosin ........................................................................................... 21 1.2. Myogenesis .......................................................................................................... 21 1.3. Skeletal muscle contraction ................................................................................. 22 1.4. Fiber type and skeletal muscle function ............................................................. 23 1.5. Myopathies .......................................................................................................... 24 2. SMALL UBIQUITIN-LIKE MODIFIER PROTEIN (SUMO) .................................. 26 2.1. The SUMO cycle and SUMO enzymes .............................................................. 27 2.2. SUMOylation regulates diverse biological processes ........................................ 30 2.3. SUMO implication in skeletal muscle pathophysiology .................................... 31 2.4. SUMO as drug targetable pathway ..................................................................... 32 3. UBIQUITIN AND THE UBIQUITIN-PROTEASOME SYSTEM ........................... 34 3.1. Ubiquitinating enzymes ....................................................................................... 35 3.2. Deubiquitinating enzymes ................................................................................... 35 3.3. E3 ubiquitin ligase MuRF1 ................................................................................. 36 3.4. SUMO pathway and Ubiquitin Proteasome System .......................................... 37 3.5. The ubiquitin and UbLs family ........................................................................... 38 4. AIMS OF THESIS ........................................................................................................ 40 4.1. Specific aims: ...................................................................................................... 40 5. METHODOLOGICAL CONSIDERATIONS ............................................................ 41 5.1. Eukaryotic cell lines ............................................................................................ 41 5.2. Rodents and human samples ............................................................................... 41 5.3. ORFs cloning in expression vectors ................................................................... 42 5.4. Side direct mutagenesis ....................................................................................... 42 5.5. Eukaryotic cells transfection ............................................................................... 43 5.6. Cells and muscle lysates ...................................................................................... 43 5.7. Immunoblotting ................................................................................................... 43 5.8. Quantitative real-time PCR ................................................................................. 44 5.9. Protein purification .............................................................................................. 44 11 5.10. Immunocytochemistry
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