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UNIVERSITY of CALIFORNIA Los Angeles Disease UNIVERSITY OF CALIFORNIA Los Angeles Disease-specific differences in glycosylation of mouse and human skeletal muscle A dissertation submitted in partial satisfaction of the requirements for the Degree of Philosophy in Cellular and Molecular Pathology by Brian James McMorran 2017 © Copyright by Brian James McMorran 2017 ABSTRACT OF THE DISSERTATION Disease-specific differences in glycosylation of mouse and human skeletal muscle by Brian James McMorran Doctor of Philosophy in Cellular and Molecular Pathology University of California, Los Angeles, 2017 Professor Linda G. Baum, Chair Proper glycosylation of proteins at the muscle cell membrane, or sarcolemma, is critical for proper muscle function. The laminin receptor alpha-dystroglycan (α-DG) is heavily glycosylated and mutations in 24 genes involved in proper α-DG glycosylation have been identified as causing various forms of congenital muscular dystrophy. While work over the past decade has elucidated the structure bound by laminin and the enzymes required for its creation, very little is known about muscle glycosylation outside of α-DG glycosylation. The modification of glycan structures with terminal GalNAc residues at the rodent neuromuscular junction (NMJ) has remained the focus of work in mouse muscle glycosylation, while qualitative lectin histochemistry studies performed three decades ago represent the majority of human muscle glycosylation research. This thesis quantifies differentiation-, species-, and disease-specific differences in mouse and human skeletal muscle glycosylation. Following differentiation of mouse myotubes, increased binding was found of lectins specific for GalNAc and O-glycans. Additionally, ii analysis of binding preferences of four GalNAc-specific lectins, which historically have been used to identify the rodent NMJ, identified differences in the glycan types bound on distinct glycoproteins by each lectin. Following differentiation of human myotubes, specific increases in binding of high mannose N-glycan specific lectin NPA, asialo core 1 O-glycan specific lectin PNA, α2,3-linked sialic acid specific lectin MAA-II and GalNAc specific lectin WFA were observed. Disease-specific differences in binding of NPA, Jac (sialylated core 1 O-glycans), TJA-I (α2,3-linked sialic acid) and WFA were observed quantitatively when comparing binding to healthy and dystrophic myotubes as well as qualitatively via lectin staining of healthy and dystrophic human skeletal muscle tissue sections. This work provides the first quantitative characterization of mouse and human muscle glycosylation, identifies lectin biomarkers for differentiation-, species-, and disease-specific differences in mouse and human muscle glycosylation, and lays the groundwork for future studies which further our understanding of the relationship between proper muscle glycosylation and muscle function. iii The dissertation of Brian James McMorran is approved. M. Carrie Miceli Stanley F. Nelson Michael A. Teitell Linda G. Baum, Committee Chair University of California, Los Angeles 2017 iv “And now that you don’t have to be perfect, you can be good” -John Steinbeck, East of Eden This work is dedicated to Ryan, without whom I would still be seeking perfect. v TABLE OF CONTENTS LIST OF FIGURES………………………………………………………………………………vii LIST OF TABLES.………………………………………………………………………..……...ix LIST OF ABBREVIATIONS……………………………………………………………………..x ACKNOWLEDGMENTS……………….…………………………..…………………………..xii VITA………………………………………………………………………...………...………....xv CHAPTER 1: Introduction………………………………………………………………..1 References……………………………………………………………..…21 CHAPTER 2: The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy……….…...………35 References……………………………………………………………..…48 CHAPTER 3: Differentiation-related glycan epitopes identify discrete domains of the muscle glycocalyx…………….……………………….…56 References……………………………………………………………..…67 CHAPTER 4: Lectin binding characterizes the healthy human skeletal muscle glycophenotype and identifies disease specific changes in dystrophic muscle…………………………………………….………..…70 References……………………………………………………..………..103 CHAPTER 5: Conclusions and future directions……………………………..……..…111 References……………………………………………………………....118 APPENDIX A: C2C12 myoblast and myotube glycotranscript expression…….……..…121 APPENDIX B: Glycan structures preferentially bound by nominally GalNAc- specific lectins: WFA, VVA-B4, SBA and DBA………….……………128 APPENDIX C: Healthy and dystrophic, human myoblast and myotube glycotranscript expression…………………………………….……...…131 vi LIST OF FIGURES CHAPTER 1 Figure 1-1: Mammalian glycosylation………………………………………………………...…15 Figure 1-2: Major sarcolemmal adhesion complexes………….…………………………………17 Figure 1-3: α-DG O-mannosylation……………………………………………………………...19 CHAPTER 2 Figure 2-1: UGC- and α7β1 integrin-mediated replacement therapy for the DGC in DMD…...….40 Figure 2-2: Glycosylation of α-DG…………………………………………….…………………41 Figure 2-3: Effects of SSPN overexpression in mdx mice on the cell surface protein expression and processing and possible outcomes of truncated dystrophin within the cell………………………………………………………………………..45 CHAPTER 3 Figure 3-1: The DGC, UGC and α7-integrin are not requisite for binding of GalNAc- specific lectins……………………………………………………………………….59 Figure 3-2: Distinct increases in binding of GalNAc-specific lectins following differentiation of C2C12 myotubes………….………………………………………60 Figure 3-3: GalNAc-specific lectins precipitate different glycoproteins………………………...61 Figure 3-4: Reduced expression of β4Galnt3, β3Galnt2, and Neu2 drive distinct changes in binding of GalNAc-specific lectins…………………………….…………..……..62 Figure 3-5: Complex N-glycans are required for binding of WFA……………………………...63 CHAPTER 4 Figure 4-1: Changes in cell surface glycosylation following differentiation of primary and immortalized healthy human myotubes………………………………..93 Figure 4-2: Disease-specific changes in lectin binding to human skeletal muscle cells…………..95 vii Figure 4-3: Different lectins precipitate different glycoproteins from healthy and dystrophic human myotubes…………………………………………………….97 Figure 4-4: Disease-specific differences in O-glycan and sialic acid-specific lectin binding to human skeletal muscle……………………………………………..99 Figure 4-5: Lectin binding to frozen versus fixed skeletal muscle………………………..……101 viii LIST OF TABLES CHAPTER 3 Table 3-1: Panel of lectins with varying specificities utilized to characterize changes in muscle glycosylation following differentiation of C2C12 myotubes………….……60 Table 3-2: Twenty-three glycosyltransferase and glycosidase transcripts upregulated following C2C12 differentiation and identified via glycotranscriptome analysis….…61 Table 3-3: Seventeen glycans with terminal GalNAc residues on CFG glycan arrays were identified as binding at least one of the four GalNAc-specific lectins…………...64 CHAPTER 4 Table 4-1: Primary and immortalized, healthy and dystrophic human myoblast cell sources …....91 Table 4-2: Panel of lectins with varying glycan structure specificities ………………………..….92 ix LIST OF ABBREVIATIONS AAV- adeno-associated virus FDA- Food and Drug Administration AChR- acetylcholine receptor FFPE- formalin-fixed, paraformaldehyde α-BTX- alpha bungarotoxin embedded α-DG- alpha-dystroglycan FKTN- fukutin B3GALNT2- β1,3-N- FKRP- fukutin-related protein Acetylgalactosaminyltransferase 2 FMD- Fukuyama muscular dystrophy B4GALNT2- β1,4-N- GAG- glycosaminoglycan Acetylgalactosaminyltransferase 2 Gal-1- galectin-1 B4GAT1- β1,4-glucuronyltransferase 1 GalNAc- N-acetylgalactosamine BMD- Becker muscular dystrophy GlcA- glucuronic acid β-DG- beta-dystroglycan GlcNAc- N-acetylglucosamine β-Xyl- beta-xylose GPI- glycosylphosphatidylinositol cGMP- cyclic guanosine monophosphate GTDC2- glycosyltransferase-like domain CMAH- cytidine monophosphate acid containing hydrolase HPA- Helix pomatia agglutinin CMD- congenital muscular dystrophy HSMC- human skeletal muscle cells ConA- Concanavalin A Hsp- heat shock proteins DBA- Dolichos biflorus agglutinin HTS- high throughput screen DGC- dystrophin-glycoprotein complex iDRMs- inducible, directly reprogrammable DMD- Duchenne muscular dystrophy myotubes DMNJ- deoxymannojirimycin ILK- integrin-linked kinase ECM- extracellular matrix x ISPD- isoprenoid synthase domain PNGaseF- Peptide-N-glycosidase F containing POMT1/2- Protein O-Mannosyltransferases Jac- jacalin 1 and 2 LARGE1/2- like- POMGNT1/2- Protein O-Linked Mannose acetylglucosaminyltransferase 1/2 N-Acetylglucosaminyltransferase 1/2 LG- laminin globular RboP- ribitol-phosphate LGMD- limb-girdle muscular dystrophy RCA 120- Ricinus communis agglutinin I MAA-II- Maackia amurensis agglutinin-II RXYLT1- Ribitol β-1,2 Xylosyltransferase MGAT5b- Mannosyl (α1,6)-Glycoprotein 1 β1,6-N-Acetyl-Glucosaminyltransferase SA-HRP- streptavidin-horseradish MTJ- myotendinous junction peroxidase Neu2- sialidase/neuraminidase 2 SBA- soybean agglutinin NeuAc- N-acetylneuraminic acid SG- sarcoglycan NeuGc- N-glycolylneuraminic acid SNA- Sambucus nigra agglutinin NMJ- neuromuscular junction SSPN- sarcospan nNOS- neuronal nitric oxide synthase TJA-I- Tricosanthes japonica agglutinin-I NO- nitric oxide TMEM5- transmembrane protein 5 NP-40- Nonidet P-40 UGC- utrophin-glycoprotein complex NPA- Narcissus psuedonarcissus agglutinin VVA- Vicia villosa agglutinin PDE-5A- phosphodiesterase-5A WFA- Wisteria floribunda agglutinin PHA-L- Phaseolus vulgaris leucoagglutinin WGA- wheat germ agglutinin pI- isoelectric point WWS- Walker-Warburg syndrome PNA- peanut agglutinin xi ACKNOWLEDGEMENTS I would like
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