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標題: Regulations of sphingolipid pathway in myogenic differentiation by interfering UDP-glucose:ceramide glucosyltransferase expression and activity
作者: Ching-Feng Yang
關鍵字: 生肌作用
glucosylceramide synthase
ganglioside GM3
cell fusion
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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.
文章公開時間: 2018-08-26
Appears in Collections:動物科學系



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