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標題: 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
The role of sphingomyelin as a membrane structural lipid in the regulation of fusion process during myoblast differentiation
作者: 賴建仰
Lai, Chien-Yang
關鍵字: sphingomyelin;神經鞘磷脂;raft;myogenesis;Src;fusion;脂筏;生肌作用;Src;細胞融合
出版社: 動物科學系所
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骨骼肌於脊椎動物扮演呼吸、移動、支持及能量代謝之功能,且佔脊椎動物大部分的身體質量;癌症末期、愛滋病及多種系統性疾病皆可導致骨骼肌異常甚至因此導致死亡。許多研究專注於解析肌肉萎縮 (muscle dystrophy) 與肌肉耗解 (muscle wasting) 機制上,如裘馨氏肌肉萎縮症 (Duchenne muscular dystrophy) 及肌肉減少症 (sarcopenia);另一領域則著重於探討調控生肌機制之因子。生肌作用晚期主要為分化之肌原母細胞拉長並進行排列聚集,然後彼此漿膜脂雙層融合形成多核之肌纖維;此過程牽涉許多訊息傳導機制及細胞反應,驅使細胞往相同方向移動並進行融合而形成單一肌纖維,然調控及造成此現象之因子尚未明瞭。於本研究中假設,神經鞘磷脂 (sphingomyelin, SM) 可能具有調節肌原母細胞分化過程中,細胞排列及融合之功能。神經鞘磷脂為神經鞘脂質 (sphingolipids) 家族含量最豐富之一員,其可與膽固醇 (cholesterol) 及糖神經鞘脂質 (glycosphingolipids) 形成脂筏,其為細胞膜上結構緻密且剛硬 (compact and rigid) 之脂雙層區域。神經鞘磷脂做為漿膜結構性脂質之一,有其固有物化 (chemo-physical) 特性,藉改變其含量及分佈應可促使細胞進行排列及膜融合,且利於多種膜蛋白共群聚 (colocalization) 並進一步影響與生肌作用相關之訊息傳導路徑。結果顯示,主要分佈於高基氏體之神經鞘磷脂合成酶 (SM synthase 1, SMS1) 及分佈於漿膜之 SMS2 於肌原母細胞分化過程中其基因表達較增生階段高。藉 SMS 抑制劑 (D609) 或 SMS siRNA 處理阻斷 SMS 活性,皆可致使 C2C12 肌原母細胞分化受阻,且抑制分化相關指標蛋白質之表達;然使用高劑量 D609 亦可抑制 C2C12 細胞增生。使用伏馬鐮孢毒素B1 (fumonisin B1, FB1) 阻斷神經醯胺 (ceramide) 合成酶活性,對 C2C12 細胞增生並無影響,然卻抑制其分化融合。利用二醯基甘油 (diacylglycerol, DAG) 結構類似物 1-oleoyl-2-acetyl -sn-glycerol (OAG) 進行處理並無法促進 C2C12 之分化且對細胞增生無影響,推測阻斷 SMS 活性所產生之抑制作用,並非減少經神經醯胺及磷脂膽鹼 (phosphatidylcholine) 合成 SM 所伴隨產生之二醯基甘油含量所導致;單獨或共同處理 FB1 及 OAG 皆無法回復 D609 所導致的肌原母細胞增生及分化受阻現象,此結果也印證前述之推測。反之,將含有人類 SMS2 序列之 pcDNA-SMS2 轉染 C2C12 肌原母細胞,可提昇 C2C12 肌原母細胞之分化與融合。細胞免疫染色試驗中使用 Alexa Fluor 555- labelled cholera toxin subunit B 標定脂筏分佈,觀察到分化之肌原母細胞脂筏群聚於細胞接觸區域;使用原子力顯微鏡 (atom force microscopy, AFM) 偵測黏滯力 (adhesion force),也發現分化之肌原母細胞於細胞接觸區域其黏滯力較低,具有較剛硬之特性,此與細胞免疫染色結果類似;前述結果驗證本研究之假說,富含 SM 之脂筏群聚於肌原母細胞之細胞間接觸邊緣,可創造有利區域環境幫助細胞往同方向進行排列;此漿膜結構改變可能與細胞間及細胞與胞外間質 (extracellular matric) 接觸之感應蛋白 integrin β3 之表達量提高、下游訊息傳導分子 Src 之活化及生肌作用中重要的影響因子 p38 相關。總結而言,由結果可推測藉改變細胞神經鞘磷脂之含量可影響 C2C12 肌原母細胞之分化及融合,因神經鞘磷脂為緻密且具極性之脂筏結構脂質,脂筏移動可導致漿膜脂雙層小區域物化特性改變,促使細胞進行排列且利於多種膜蛋白進行群聚,使經細胞間及細胞與胞外間質接觸下游與生肌相關之訊息傳導路徑受到誘發,藉其所扮演的多種功能促進肌原母細胞之分化及融合。

Skeletal muscle accounts for the most of body mass and function in moving, supporting, breathing, and energy metabolism in vertebrates. Dysfunction of skeletal muscle such as cachexia with advanced cancers, AIDS, and other chronic progressive diseases may lead to death. In contrast to the mechanisms of muscle dystrophy or wasting progress such as Duchenne muscular dystrophy and sarcopenia, another focus of muscle functionality is myogenic regulation. The later event of myogenesis is that differentiating elongated myoblasts start to align locally toward same directions and then the adjacent myoblasts integrate membranes to fuse into multinucleated myofibers. However, the factors and driving forces to ensure the fusion process are still poorly defined. In the study we hypothesized that the alignment and fusion process during myoblast differentiation is regulated by sphingomyelin (SM). Sphingomyelin, the most abundant form of sphingolipids, can interact with cholesterol and glycosphingolipids to form compact and rigid membrane microdomains, rafts. We proposed changes of cellular SM level and raft distribution functioning to facilitate the alignment and membrane integration of myoblasts during fusion process, due to its chemo-physical characteristics as a structural lipid, colocalization with various membrane proteins, and thereby downstream relays with the myogenic signaling. Results showed that expression of both sphingomyelin synthase 1 (SMS1) and SMS2 transcript increased with the progress of C2C12 myoblast differentiation. Blockade of SMS activity by inhibitor D609 or by siRNA intervention, severely inhibited the fusion process as evidenced by morphological changes in accordance with differentiation marker expressions including myogenin, myosin heavy chain (MHC), and caveolin-3. However, the SMS activity interruption particularly at a high level of D609 also suppressed C2C12 cell proliferation. Treatment of fumonisin B1 (FB1) to block ceramide synthase activity also suppressed the fusion process but had no effect on cell proliferation. The results suggested that sphingomyelin abundance regardless to intermediate ceramide per se that has been shown to inhibit myogenesis is the main cause of C2C12 differentiation suppressed by manipulating SMS activity. Treatment of diacylglycerol (DAG) analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG) also failed to promote C2C12 differentiation and proliferation, suggesting that inhibition of C2C12 differentiation by interrupting SMS activity can not be attributed to suppressed DAG production from the SMS catalytic reaction of ceramide and phosphatidylcholne into SM. This suggestion was further confirmed by the failure of FB1 or OAG alone or combination of both to rescue the suppression of C2C12 proliferation and differentiation induced by D609. To further fortify the evidences, human SMS2 constructed as pcDNA-SMS2 was transduced into C2C12 cells, which thereafter demonstrated dramatic acceleration of fusion process. Immunocytochemical studies suggested that raft microdomains detected by Alexa Fluor 555-labelled cholera toxin subunit B staining migrated and clustered toward the approaching and junction edges around the membranes of differentiating myoblasts. The adhesion force detected by atom force microscopy confirmed a similar result suggesting that the approaching or contact junction edges of adjacent cells were more compact and rigid than the other regions within the same cells. These observations also suggested that abundance of rafts rich of SM distribution or cluster along the approaching and junction edges of adjacent myoblasts can create a facilitated microenvironment in local regions to drive cells migrating in alignment for fusion. These structural membrane mechanic alterations were consistently associated with upregulation of integrin β3, a sensing molecule of cell-cell/extracellular matrix (ECM) contact and downstream signaling molecule, Src activation, and furthermore p38, a critical signaling effector in myogenic program. In conclusion, results in the study suggested that alterations of SM level function to facilitate the alignment and fusion process of myoblast differentiation by serving as a rigid and polar structural lipid in membrane rafts, whose abundance and distribution affect chemo-physical characteristics of the membranes to drive cells moving in alignment for fusion and to render colocalization with various membrane proteins and thereby regulate the downstream myogenic signaling with cell-cell/ECM contact and approaching.
其他識別: U0005-1808201023573200
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