臺灣博碩士論文加值系統

輔仁大學一百學年度第一學期碩士論文摘要
系( 所 )別：營養科學系 研究生：張佑瑛
論文名稱：鐵營養狀況對大鼠骨骼肌mRNA轉譯作用之調節機轉
指導教授：劉奕方 博士
中文摘要
本實驗室先前研究發現膳食缺鐵可使大鼠肌肉組織中細胞質硫醇鹼基修飾之tRNA的表現與其硫醇鹼基修飾作用減少，因tRNA分子上鹼基修飾作用受限與蛋白質的生合成速率有關。因此本論文之研究目的主要在探討膳食鐵量攝取不足對於大鼠肌肉組織中mRNA轉譯作用調控之影響，藉此瞭解膳食鐵缺乏改變硫醇鹼基修飾tRNA表現與修飾作用對於mRNA轉譯作用之關係。據此目的而設計此動物實驗，將Wistar 雄性離乳四週齡之大鼠，依其體重分為控制、膳食鐵中度缺乏、膳食鐵嚴重缺乏與其對飼育四組 (n=6)，根據AIN93G配方調配飼料，飼養四週後犧牲，收集血液測定鐵營養狀況指標，取一塊後肢肌肉進行胞器分離，所得之細胞質部分以西方轉漬法測定內質網壓力指標、細胞質eIF2α/PERK磷酸化路徑、eEF2蛋白質磷酸化作用與mTOR訊息路徑相關蛋白質的表現；另一塊肌肉組織則採用酸性條件進行總RNA萃取後，再以北方墨點法測定其攜帶或未攜帶胺基酸之tRNA表現。結果顯示：膳食鐵嚴重缺乏大鼠之血紅素、血清鐵與運轉鐵蛋白的飽和度均顯著性減少分別為62%、79%與82%，而總鐵結合能力則明顯增加為控制組的1.1倍，表示大鼠有明顯缺鐵性貧血的現象。缺鐵大鼠肌肉細胞質中磷酸化形式之蛋白質p-mTOR 、p-S6、p-4E-BP1的表現量均不受缺鐵而具有顯著性的影響，但在膳食鐵嚴重缺乏大鼠之後肢肌肉細胞質中GRP78（或稱Bip）以及下游調節蛋白質之磷酸化p-PERK 、p-eIF2α與非磷酸化形式eIF2α蛋白質的表現量皆顯著性增加分別為74%、75% 、41%和43%。此外，膳食鐵嚴重缺乏肌肉組織細胞質中磷酸化形式之eEF2蛋白質表現量也具有顯著性增加為69%。以10 mg Fe/kg diet飼料飼養大鼠作為膳食鐵中度缺乏的方式，可使大鼠之血紅素值減少為19%，但對於大鼠肌肉組織中GRP78與eIF2α蛋白質、磷酸化形式之p-PERK、p-eIF2α、p-eEF2、p-mTOR 、p-S6與p-4E-BP1蛋白質的表現量沒有明顯的影響。另一方面，採用酸性條件進行總RNA的萃取與酸性電泳分析，可有效地區分出細胞質tRNALys(UUU)攜帶胺基酸之charged-tRNA與未攜帶胺基酸之uncharged-tRNA分子型式。然而以charged-tRNALys(UUU)、uncharged-tRNALys(UUU)或者total tRNALys(UUU)的方式進行定量時，經統計分析後其平均值表現量均未達統計上的顯著差異，但三者的平均表現量則分別減少28%、27%、28%。此外，其他細胞質或粒線體tRNA分子主要是以uncharged-tRNA形式存在於大鼠肌肉組織中，表示膳食鐵嚴重性缺乏時對於tRNA分子進行aminoacylation的作用可能沒有任何的影響。綜合上述，膳食鐵嚴重攝取不足時會藉由引起的內質網壓力而促進ERPK的活化而導致eIF2蛋白質的磷酸化作用以及eEF2蛋白質的磷酸化作用，推測因此而抑制轉譯作用起始與延長反應受阻進而導致蛋白質合成速率降低有關。
關鍵字：轉譯作用、mTOR訊息路徑、tRNA、eIF2α/PERK訊息路徑、eEF2

Mechanisms by which iron status regulates mRNA translation in skeletal muscle of rats
Abstract
Our previous study demonstrated that cytosol thiouridine-containing tRNAs expression and it’s tion-modification were specifically decreased in iron-dificient skeletal muscle. Because the nucleotide modification of tRNA may relate to protein synthesis, hence in this study we investigated the regulation of dietary iron intake on mRNA translation in skeletal muscle. It is to understand the relationship between thio-midification of thiouridine-containing tRNAs and the mRNA translation in the muscles of iron deficency rats. In this study, male weanling Wistar rats were divided into four group by weight：control (AI) , moderate iron dificient (MID) , severe iron dificient (ID) and severe iron dificient paired-fed (IPF) (n=6). The rats were euthanized after feeding with AIN93G formula four weeks. Blood samples were collected to measure iron status and one of the skeletal muscle measured the cytosol ER strss marker, eIF2α/PERK phosphorylation pathway, the phosphorylation of p-eEF2 and relation protein of mTOR signaling by Western blotting. Another of the skeletal muscles measured the charged- tRNA and uncharged-tRNA expression by acid extraction and Northern blotting. The results showed in ID rats the hematological indices of iron status (hemoglobin, serum iron and transferrin saturation) decreased about 62%, 79% and 82% , respectively. Nevertheless, the TIBC (total iron binding capacity) increased 1.1 fold compared with control group. This indicated ID rats have severe iron-deficiency anemia. The expression of p-mTOR, p-S6 and p-4EBP1 proteins in cytosol of ID rat’s muscle were not affected. However, the ER stress marker GRP78 (known as Bip) and it’s downsteam target p-PERK, p-eIF2α and eIF2α protein siginificantly increased 74%, 75%, 41% and 43% in muscles of ID rats. In addition, the expression of phosphorylation of p-eEF2 also siginificantly increased 69% in muscle of ID rats. In the moderate iron-deficient group which fed 10 mg Fe/kg diet, the hemoglobin declined to 19% of control group, while the GRP78, eIF2α, the phosphorylation of p-PERK, p-eIF2α, p-eEF2, p-mTOR, p-S6 and p-4E-BP protein levels were not affected. Furthermore, we analysed the total RNA by acid extraction and acid electrophoresis which could effectively differentiate cytosol charged-tRNALys(UUU) and uncharged-tRNALys(UUU). No matter the expresion of charged-tRNALys(UUU), uncharged-tRNALys(UUU) or total tRNALys(UUU) were not siginificantly different in iron-deficient group, but the mean experssion respectively decreased 28%, 27% and 28%. However, the other cytosol tRNA and mitochondrial tRNALys(UUU) and tRNAGlu(UUC) all could not be discriminated charged or uncharged form tRNA. We speculated that the other cytosol and mitochondrial tRNA excepte cytosol tRNALys(UUU) expressed the uncharged-tRNA in skeletal muscles of the rat. These results indicated severe iron dificiency may not have any sigicificant influence on tRNA aminoacylation. In conclusion, our study demonstrated that severe iron dificiency induced the ER stress and then activated the endoplasmic reticulum kinase PERK, leading to phosphorylation of p-eIF2α and p-eEF2 to inhibit initiation and elongation of mRNA translation and reducded the rate of protein synthesis.

Key words：mRNA translation , mTOR signaling , tRNA , eEF2,
eIF2α/PERK pathway

目 錄
頁次
中文摘要 i
英文摘要 iii
誌 謝 vi
目 錄 vii
圖目錄 ix
表目錄 x
縮寫名詞表 xi

第一章 前 言 1

第二章 文獻回顧 2
第一節、真核生物Messenger RNA轉譯的機制與其調控作用 2
一、轉譯反應之機制 2
二、轉譯起始作用之調控與蛋白質合成之關係 3
第二節、生物中Transfer RNA的表現與其鹼基修飾作用對於蛋白質合成之重要性 6
一、Transfer RNA之特性與生理功能 6
二、Transfer RNA鹼基修飾作用與轉譯之關係 9
第三節、低氧壓對於蛋白質生合成反應與調控 12
一、低氧壓引起內質網壓力對於未摺疊蛋白質反應之影響 12
二、未摺疊蛋白質反應與轉譯起始作用調控之關係 14
第四節、鐵營養狀況對肌肉生理與生化之影響 17
一、鐵營養狀況對動物組織能量代謝之影響 17
二、鐵營養狀況對肌肉Transfer RNA表現與鹼基修飾作用之影響 18
三、細胞鐵量不足與mTOR訊息路徑之關係 19
第五節、實驗動機 20

第三章 材料與方法 21
第一節、動物飼養與飼料組成 21
第二節、實驗設計與分析項目 22
第三節、樣品收集與處理 25
一、血液生化分析 25
二、組織中細胞質蛋白質表現分析 27
三、組織中非編譯RNA之分析 33
第四節、統計分析 40

第四章 結 果 41
第一節、大鼠生長狀況與血液鐵營養指標 41
第二節、鐵營養狀況對大鼠肌肉p-mTOR、p-4E-BP1與p-S6蛋白質表現之影響 42
第三節、鐵營養狀況對大鼠肌肉p-eIF2α、eIF2α及p-eEF2蛋白質表現之影響 43
第四節、鐵營養狀況對大鼠肌肉GRP78及p-PERK蛋白質表現之影響 43
第五節、鐵營養狀況對大鼠肌肉細胞質charged-tRNA與uncharged-tRNA表現之影響 44
第六節、鐵營養狀況對於大鼠肌肉粒線體charged-tRNA與uncharged-tRNA表現的影響 46

第五章 討論與結論 64
第一節、缺鐵引起肌肉內質網壓力的產生對大鼠肌肉mRNA轉譯起始與延長調節之影響 64
第二節、缺鐵引起大鼠肌肉產生內質網壓力對於肌肉生理生化代謝之影響 69
第三節、鐵營養狀況對大鼠肌肉mTOR訊號路徑之影響與蛋白質生成關係 71
第四節、缺鐵改變大鼠肌肉tRNA表現與鹼基修飾作用與轉譯作用之關係 73
第六節、結 論 75

第六章 參考文獻 77

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