Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/90324
標題: Regulations of sphingolipid pathway in myogenic differentiation by interfering UDP-glucose:ceramide glucosyltransferase expression and activity
調控葡萄糖神經醯胺合成酶以探討神經鞘脂質途徑對生肌作用之影響
作者: Ching-Feng Yang
楊慶逢
關鍵字: 生肌作用
葡萄糖神經醯胺合成酶
神經節苷脂GM3
細胞融合
myogenesis
glucosylceramide synthase
ganglioside GM3
cell fusion
引用: 尹相姝。2006。人體組織學(第三版)。藝軒圖書出版社。台北縣。 劉祖誠。2009。過度餵飼引發白肉種雞與台灣土雞產蛋性能低落-免疫細胞異嗜球相關功能之探討。碩士論文。中興大學。台中。 賴建仰。2010。結構性脂質神經鞘磷脂調節肌原母細胞分化時期之融合過程。碩士論文。中興大學。台中。 Abe, A., N. S. Radin, and J. A. Shayman. 1996. Induction of glucosylceramide synthase by synthase inhibitors and ceramide. Biochim. Biophys. Acta 1299:333-341. Anastasia, L., N. Papini, F. Colazzo, G. Palazzolo, C. Tringali, L. Dileo, M. Piccoli, E. Conforti, C. Sitzia, E. Monti, M. Sampaolesi, G. Tettamanti, and B. Venerando. 2008. NEU3 sialidase strictly modulates GM3 levels in skeletal myoblasts C2C12 thus favoring their differentiation and protecting them from apoptosis. J. Biol. Chem. 283:36265-36271. Baran, Y., J. Bielawski, U. Gunduz, and B. Ogretmen. 2011. Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation. J. Cancer Res. Clin. Oncol. 137:1535-1544. Bassi, R., P. Viani, P. Giussani, L. Riboni, and G. Tettamanti. 2001. GM3 ganglioside inhibits endothelin-1-mediated signal transduction in C6 glioma cells. FEBS Letters 507:101-104. Becciolini, L., E. Meacci, C. Donati, F. Cencetti, E. Rapizzi, and P. Bruni. 2006. Sphingosine 1-phosphate inhibits cell migration in C2C12 myoblasts. Biochim. Biophys. Acta 1761:43-51. Bentzinger, C. F., Y. X. Wang, and M. A. Rudnicki. 2012. Building muscle: Molecular regulation of myogenesis. Cold Spring Harb. Perspect. Biol. doi:10.1101/cshperspect.a008342. Bieberich, E., B. Freischutz, M. Suzuki, and R. K. Yu. 1999. Differential effects of glycolipid biosynthesis inhibitors on ceramide-induced cell death in neuroblastoma cells. J. Neurochem. 72:1040-1049. Biressi, S., C. R. R. Bjornson, P. M. M. Carlig, K. Nishijo, C. Keller, and T. A. Rando. 2013. Myf5 expression during fetal myogenesis defines the developmental progenitors of adult satellite cells. Dev. Biol. 379:195-207. Bismuth, K., and F. Relaix. 2010. Genetic regulation of skeletal muscle development. Exp. Cell Res. 316:3081-3086. Bruni, P., and C. Donati. 2008. Pleiotropic effects of sphingolipids in skeletal muscle. Cell. Mol. Life Sci. 65:3725-3736. Calise, S., S. Blescia, F. Cencetti, C. Bernacchioni, C. Donati, and P. Bruni. 2012. Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: Role of S1P receptors. Biochim. Biophys. Acta 1823:439-450. Cambron, L. D., and K. C. Leskawa. 1994. Glycosphingolipids during skeletal muscle differentiation: Comparison of normal and fusion-defective myoblasts. Mol. Cell. Biochem. 130:173-185. Carosio, S., M. G. Berardinelli, M. Aucello, and A. Musaroò. 2011. Impact of ageing on muscle cell regeneration. Ageing Res. Rev. 10:35-42. Chai, L., R. P. McLaren, A. Byrne, W. L. Chung, Y. Huang, M. R. Dufault, J. Pacheco, S. Madhiwalla, X. Zhang, M. Zhang, B. A.Teicher, K. Carter, S. H. Cheng, J. P. Leonard, Y. Xiang, M. Vasconcelles, M. A. Goldberg, D. P. Copeland, K. W. Klinger, J. Lillie, S. L. Madden, and Y. A. Jiang. 2011. The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function. Int. J. Oncol. 38:701-711. Champigny, M. J., R. Perry, M. Rudnicki, and S. A. Igdoura. 2005. Overexpression of MyoD-inducible lysosomal sialidase (neu1) inhibits myogenesis in C2C12 cells. Exp. Cell Res. 311:157-166. Chen, S. E., B. Jin, and Y. P. Li. 2007. TNF-α regulates myogenesis and muscle regeneration by activating p38 MAPK. Am. J. Physiol. Cell Physiol. 292:C1660-C1671. Daniotti, J. L., and R. Iglesias-Bartolomé. 2011. Metabolic pathways and intracellular trafficking of gangliosides. IUBMB Life 63:513-520. Dawson, G. 1972. Glycosphingolipid levels in an unusual neurovisceral storage disease characterized by lactosylceramide galactosyl hydrolase deficiency: lactosylceramidosis. J. Lipid Res. 13:207-219. Donati, C., E. Meacci, F. Nuti, L. Becciolini, M. Farnararo, and P. Bruni. 2005. Sphingosine 1-phosphate regulates myogenic differentiation: A major role for S1P2 receptor. FASEB J. 19:449-451. Fanzani, A., R. Guilian, F. Colombo, D. Zizioli, M. Presta, A. Preti, and S. Marchesini. 2003. Overexpression of cytosolic sialidase Neu2 induces myoblast differentiation in C2C12 cells. FEBS Lett. 547:183-188. Gangoiti, P., C. Bernacchioni, C. Donati, F. Cencetti, A. Ouro, A. Gómez-Muñoz, and P. Bruni. 2012. Ceramide 1-phosphate stimulates proliferation of C2C12 myoblasts. Biochimie 94:597-607. Ghauharali-van der Vlugt, K., M. Langeveld, A. Poppema, S. Kuiper, C. E. M. Hollak, J. M. Aerts, and J. E. M. Groener. 2008. Prominent increase in plasma ganglioside GM3 is associated with clinical manifestations of type I Gaucher disease. Clinica. Chimica. Acta 389:109-113. Hannun, Y. A., and L. M. Obeid. 2008. Principles of bioactive lipid signalling: Lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9:139-150. He, X., A. Dagan, S. Gatt, and E. H. Schuchman. 2005. Simultaneous quantitative analysis of ceramide and sphingosine in mouse blood by naphthalene-2,3-dicarboxyaldehyde derivatization after hydrolysis with ceramidase. Anal. Biochem. 340:113-122. Huang, W. C., C. C. Tsai, C. L. Chen, T. Y. Chen, Y. P. Chen, Y. S. Lin, P. J. Lu, C. M. Lin, S. H. Wang, C. W. Tsao, C. Y. Wang, Y. L. Cheng, C. Y. Hsieh, P. C. Tseng, and C. F. Lin. 2011. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J. 25:3661-3673. Hutcheson, D. A., J. Zhao, A. Merrell, M. Haldar, and G. Kardon. 2009. Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for β-catenin. Genes Dev. 23:997-1013. Janot, M., A. Audfray, C. Loriol, A. Germot, A. Maftah, and F. Dupuy. 2009. Glycogenome expression dynamics during mouse C2C12 myoblast differentiation suggests a sequential reorganization of membrane glycoconjugates. BMC Genomics 10:483. doi:10.1186/1471-2164-10-483. Janssen, J., S. B. Heymsfield, Z. M. Wang, and R. Ross. 2000. Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr. J. Appl. Physiol. 89:81-88. Jayadev, S., H. L. Hayter, N. Andrieu, C. J. Gamard, B. Liu, R. Balu, M. Hayakawa, F. Ito, and Y. A. Hannun. 1997. Phospholipase A2 is necessary for tumor necrosis factor α-induced ceramide generation in L929 cells. J. Biol. Chem. 272:17196-17203. Knight, J. D. R., and R. Kothary. 2011. The myogenic kinome: Protein kinases critical to mammalian skeletal myogenesis. Skeletal Muscle 1:29. doi: 10.1186/1471-2164-10-483. Komori, H., S. Ichikawa, Y. Hirabayashi, and M. Ito. 2000. Regulation of UDP-glucose:ceramide glucosyltransferase-1 by ceramide. FEBS Letters 475:247-250. Kuang, S., M. A. Gillespie, and M. A. Rudnicki. 2008. Niche regulation of muscle satellite cell self-renewal and differentiation. Cell Stem Cell 2:22-31. Lahiri, S., and A. H. Futerman. 2007. The metabolism and function of sphingolipids and glycosphingolipids. Cell. Mol. Life Sci. 64:2270-2284. Leroy, M. C., J. Perroud, B. Darbellay, L. Bernheim, and S. Konig. 2013. Epidermal growth factor receptor down-regulation triggers human myoblast differentiation. PLoS ONE 8:e71770. doi:10.1371/journal.pone.0071770. Leskawa, K. C., and E. L. Hogan. 1990. Regulation of glycolipid synthesis during differentiation of clonal murine muscle cells. Mol. Cell. Biochem. 96:163-173. Liour, S. S., and R. K. Yu. 2002. Differential effects of three inhibitors of glycosphingolipid biosynthesis on neural differentiation of embryonal carcinoma stem cells. Neurochem. Res. 27:1507-1512. Liu, Y. Y., and Y. T. Li. 2013. Ceramide glycosylation catalyzed by glucosylceramide synthase and cancer drug resistance. Adv. Cancer Res. 117:59-89. Mathews, C. K., K. E. van Holde, and K. G. Ahern. 2000. BIOCHEMISTRY. Third Edition. Addison-Wesley Publishing Company. San Francisco. USA. Mauro, A. 1961. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9:493-495. Meacci, E., F. Nuti, C. Donati, F. Cencetti, M. Farnararo, and P. Bruni. 2008. Sphingosine kinase activity is required for myogenic differentiation of C2C12 myoblasts. J. Cell. Physiol. 214:210-220. Meadows, K. A., J. M. P. Holly, and C. E. H. Stewart. 2000. Tumor necrosis factor-α-induced apoptosis is associated with suppression of insulin-like growth factor binding protein-5 secretion in differentiating murine skeletal myoblasts. J. Cell. Physiol. 183:330-337. Mebarek, S., H. Komati, F. Naro, C. Zeiller, M. Alvisi, M. Lagarde, A. Prigent, and G. Némoz. 2007. Inhibition of de novo ceramide synthesis upregulates and phospholipase D and enhances myogenic differentiation. J. Cell Sci. 120:407-416. Miyagi, T., and K. Yamaguchi. 2012. Mammalian sialidases: physiological and pathological roles in cellular functions. Glycobiology 22:880-896. Nagata, Y., H. Kobayashi, M. Umeda, N. Ohta, S. Kawashima, P. S. Zammit, and R. Matsuda. 2006a. Sphingomyelin levels in the plasma membrane correlate with the activation state of muscle satellite cells. J. Histochem. Cytochem. 54:375-384. Nagata, Y., T. A. Partridge, R. Matsuda, and P. S. Zammit. 2006b. Entry of muscle satellite cells into the cell cycle requires sphingolipid signaling. J. Cell Biol. 174:245-253. Nicolae, I., C. D. Nicolae, O. A. Coman, M. Ştefǎnescu, L. Coman, and C. Ardeleanu. 2011. Serum total gangliosides level: Clinical prognostic implication. Rom. J. Morphol. Embryol. 52:1277-1281. Otto, A., H. Collins-Hooper, and K. Patel. 2009. The origin, molecular regulation and therapeutic potential of myogenic stem cell populations. J. Anat. 215:477-497. Paller, A. S., S. L. Arnsmeier, M. Alvarez-Franco, and E. G. Bremer. 1993. Ganglioside GM3 inhibits the proliferation of cultured keratinocytes. J. Invest. Dermatol. 100:841-845. Papini, N., A. Luigi, C. Tringali, L. Dileo, I. Carubelli, M. Sampaolesi, E. Monti, G. Tettamanti, and B. Venerando. 2012. MmNEU3 sialidase over-expression in C2C12 myoblasts delays differentiation and induces hypertrophic myotube formation. J. Cell. Biochem. 113:2967-2878. Parker, M. H., P. Seale, and M. A. Rudnicki. 2003. Looking back to the embryo: Defining transcriptional networks in adult myogenesis. Nat. Rev. Genet. 4:495-505. Rapizzi, E., C. Donati, F. Cencetti, P. Nincheri, and P. Bruni. 2008. Sphingosine 1-phosphate differentially regulates proliferation of C2C12 reserve cells and myoblasts. Mol. Cell. Biochem. 314:193-199. Relaix, F., and P. S. Zammit. 2012. Satellite cells are essential for skeletal muscle regeneration: The cell on the edge returns centre stage. Development 139:2845-2856. Saito, M., and A. Rosenberg. 1982. Glycolipids and their developmental patterns in chick thigh and leg muscles. J. Lipid Res. 23:3-8. Salvatori, L., F. Caporuscio, G. Coroniti, G. Starace, L. Frati, M. A. Russo, and E. Petrangeli. 2009. Down-regulation of epidermal growth factor receptor induced by estrogens and phytoestrogens promotes the differentiation of U2OS human osteosarcoma cells. J. Cell. Physiol. 220:35-44. Sando, G. N., E. J. Howard, and K. C. Madison. 1996. Induction of ceramide glucosyltransferase activity in cultured human keratinocytes: Correlation with culture differentiation. J. Biol. Chem. 271:22044-22051. Santana, P., L. A. Peña, A. Haimovitz-Friedman, S. Martin, D. Green, M. McLoughlin, C. Cordon-Cardo, E. H. Schuchman, Z. Fuks, and R. Kolesnick. 1996. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation -induced apoptosis. Cell 86:189-199. Santin, A. D., M. H. Ravindranath, S. Bellone, S. Muthugounder, M. Palmieri, T. J. O'Brien, J. Roman, M. J. Cannon, and S. Pecorelli. 2004. Increased levels of gangliosides in the plasma and ascitic fluid of patients with advanced ovarian cancer. Br. J. Obstet. Gynaecol. 111:613-618. Sato, K., and T. Miyagi. 1996. Involvement of an endogenous sialidase in skeletal muscle cell differentiation. Biochem. Biophys. Res. Commun. 221:826-830. Simpson, M. A., H. Cross, C. Proukakis, D. A. Priestman, D. C. A. Neville, G. Reinkensmeier, H. Wang, M. Wiznitzer, K. Gurtz, A. Verganelaki, A. Pryde, M. A. Patton, R. A. Dwek, T. D. Butters, F. M. Platt, and A. H. Crosby. 2004. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat. Genet. 36:1225-1229. Smith, W. L., and A. H. Merrill, Jr. 2002. Sphingolipid metabolism and signaling minireview series. J. Biol. Chem. 277:25841-25842. Song, M., W. Zang, B. Zhang, J. Cao, and G. Yang. 2012. GCS overexpression is associated with multidrug resistance of human HCT-8 colon cancer cells. J. Exp. Clin. Cancer Res. 31:23. Stockmann-Juvala, H., and K. Savolainen. 2008. A review of the toxic effects and mechanisms of action of fumonisin B1. Hum. Exp. Toxicol. 27:799-809. Tagami, S., J. Inokuchi, K. Kabayama, H. Yoshimura, F. Kitamura, S. Uemura, C. Ogawa, A. Ishii, M. Saito, Y. Ohtsuka, S. Sakaue, and Y. Igarashi. 2002. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 277:3085-3092. Tajbakhsh, S. 2009. Skeletal muscle stem cells in developmental versus regenerative myogenesis. J. Intern. Med. 266:372-389. Uemura, K., E. Sugiyama, C. Tamai, A. Hara, T. Taketomi, and N. S. Radin. 1990. Effect of an inhibitor of glucosylceramide synthesis on cultured rabbit skin fibroblasts. J. Biochem. 108:525-530. van Meer, G., D. R. Voelker, and G. W. Feigenson. 2008. Membrane lipids: Where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9:112-124. Wang, X., P. Sun, and A. S. Paller. 2003. Ganglioside GM3 blocks the activation of epidermal growth factor receptor induced by integrin at specific tyrosine sites. J. Biol. Chem. 278:48770-48778. Wang, X., Z, Rahman, P. Sun, E. Meuillet, D. George, E. G. Bremer, A. Al-Qamari, and A. S. Paller. 2001. Ganglioside modulates ligand binding to the epidermal growth factor receptor. J. Invest. Dermatol. 116:69-76. Watanabe, R., K. Wu, P. Paul, D. L. Marks, T. Kobayashi, M. R. Pittelkow, and R. E. Pagano. 1998. Up-regulation of glucosylceramide synthase expression and activity during human keratinocyte differentiation. J. Biol. Chem. 273:9651-9655. Woodcock, J. 2006. Sphingosine and ceramide signalling in apoptosis. IUBMB Life 58:462-466. Xie, P., Y. F. Shen, Y. P. Shi, S. M. Ge, Z. H. Gu, J. Wang, H. J. Mu, B. Zhang, W. Z. Qiao, and K. M. Xie. 2008. Overexpression of glucosylceramide synthase in associated with multidrug resistance of leukemia cells. Leukemia Res. 32:475-480. Yin, H., F. Price, and M. A. Rudnicki. 2013. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93:23-67. Yu, R. K., Y. T. Tsai, and T. Ariga. 2012. Functional roles of gangliosides in neurodevelopment: An overview of recent advances. Neurochem. Res. 37:1230-1244. Zhu, L., E. Shimizu, X. Zhang, N. C. Partridge, and L. Qin. 2011. EGFR signaling suppresses osteoblast differentiation and inhibits expression of master osteoblastic transcription factors Runx2 and Osterix. J. Cell. Biochem. 112:1749-1760.
摘要: 生肌作用 (myogenesis) 是一個漸進的過程,當肌原母細胞 (myoblasts) 進行分化時,細胞會先脫離細胞週期 (cell cycle),接著開始表現肌肉特異性轉錄因子 (muscle-specific transcription factors),進而形成肌細胞 (myocytes)。肌細胞接著會遷徙、排列,並彼此融合,最終形成具有多核的肌纖維 (myofibers)。神經鞘脂質 (sphingolipids) 為一個龐大的脂質家族,該脂質家族的成員普遍存在於細胞中。除了作為結構性分子之外,成員多具生物活性,參與調節許多細胞功能,如細胞增生、分化、遷移及凋亡等。有許多文獻指出,神經鞘脂質家族成員也參與生肌作用調節。神經鞘脂質的代謝過程相當複雜,位於神經鞘脂質代謝過程中心的神經醯胺 (ceramide),可經由不同酵素催化合成出不同的神經鞘脂質家族成員。先前實驗室已分別探討神經醯胺代謝成神經鞘磷脂 (sphingomyelin),以及神經醯胺代謝成神經鞘胺醇 (sphingosine) 這兩條代謝路徑對生肌作用之影響。文獻指出,隨著肌原母細胞分化天數的增加,細胞中的神經節苷脂GM3 (ganglioside GM3, GM3) 含量也隨之增加,顯示神經節苷脂GM3在肌肉發育過程中扮演相關調節角色。因此本研究重點藉由調控參與此代謝路徑的第一個酵素:葡萄糖神經醯胺合成酶 (glucosylceramide synthase),以探討神經醯胺代謝成神經節苷脂GM3這條代謝路徑對生肌作用之影響。 研究結果顯示:外源性添加10μM GM3可促進肌小管 (myotubes) 的形成;當GM3添加劑量增加至50μM時,則會使肌小管的形成受阻。添加10μM葡萄糖神經醯胺合成酶抑制劑DL-PDMP (DL-threo-Phenyl-2-Decanoylamino-3-Morpholino-1-Propanol) 時,會使肌小管的形成受阻;當DL-PDMP添加劑量增加至50μM,則會使肌原母細胞大量死亡。10μM DL-PDMP也會使分化晚期細胞中神經醯胺、神經鞘胺醇及神經鞘磷脂含量顯著增加 (P < 0.05)。葡萄糖神經醯胺合成酶蛋白質之表現,隨著分化時間的增加,其表現量呈現先增後減的現象;利用siRNA轉染來干擾葡萄糖神經醯胺合成酶會使其蛋白質表現減少、肌管的形成受阻,也會使死亡肌原母細胞數量增加;但siRNA轉染並未對分化晚期肌原母細胞中神經醯胺、神經鞘胺醇及神經鞘磷脂含量造成影響 (P > 0.05)。綜合以上結果,葡萄糖神經醯胺合成酶可能是藉由直接減少肌原母細胞中神經醯胺含量,進而間接影響神經鞘脂質家族其他成員的含量,最終影響生肌作用的進行。
Myogenesis is a multistep process. When inducd for differentiation, myoblasts exit from cell cycle, express muscle-specific transcription factors, and turn into myocytes. Later, myocytes migrate, align and fuse with other myocytes to form multi-nucleated myofibers finally. Sphingolipids is a class of lipids which is widespread in cells. Not only serving as important structural molecules, sphingolipids also act as bioactive molecules to regulate a variety of cell functions including proliferation, differentiation, migration and apoptosis. Numerous studies have shown that sphingolipids also regulate skeletal muscle differentiation. The processes of sphingolipid metabolism and synthesis are complicated, in which ceramide is situated as the central molecule in the catabolic and anabolic pathways of sphingolipids. Previously, we conducted a series of studies to investigate the role of ceramide metabolism into sphingomyelin and from sphingosine in the regulation of myogenesis. Past studies showed that along myoblast differentiation, cellular ganglioside GM3 abundance also increases, suggesting that gangliside GM3 may play a role in skeletal muscle differentiation. The present study was focused on the role of ceramide metabolism into gangliosides – by manipulating glucosylceramide synthase activity and gene expression, the first enzyme in ceramide metabolism into ganglioside GM3. Results showed that 10μM ganglioside GM3 promoted myotube formation; however, 50μM ganglioside GM3 inhibited myogenic differentiation into myotubes. Treatment of DL-PDMP (DL-threo-Phenyl-2-Decanoylamino-3-Morpholino-1-Propanol) at 10μM level inhibited myotube formation, and 50μM DL-PDMP further induced cell death. Consistently, treatment of DL-PDMP at 10μM level also increased cellular ceramide, sphingosine and sphingomyelin content (P < 0.05). UDP-glucose:ceramide glucosylceramide synthase expression increased and then declined along differentiation program. Intervention of siRNA suppressed glucosyltransferase expression, inhibited myotube formation, and also slightly induced cell death. However, siRNA intervention exerted a marginal effect on promoting cellular ceramide, sphingosine and sphingomyelin content (P > 0.05). In conclusion, UDP-glucose:ceramide glucosyltransferase regulates myogenic differentiation, probably by affecting relative content of sphingolipid members.
URI: http://hdl.handle.net/11455/90324
文章公開時間: 2018-08-26
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