過氧化氫體於肌肉形成過程及癌症惡質症的調控與角色;The Regulation and Role of Peroxisome in Myogenesis and Cancer Cachexia

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题名:	過氧化氫體於肌肉形成過程及癌症惡質症的調控與角色;The Regulation and Role of Peroxisome in Myogenesis and Cancer Cachexia
作者:	吳傳喆;Wu, Chuan-Che
贡献者:	生命科學系
关键词:	過氧化氫體;肌肉生成過程;粒線體;癌症惡質症;Peroxisome;Myogenesis;Mitochondria;Cancer cachexia
日期:	2022-08-08
上传时间:	2022-10-04 11:03:17 (UTC+8)
出版者:	國立中央大學
摘要:	過氧化氫體(Peroxisome)為細胞代謝之重要胞器，其功能包括協助細胞進行呼吸作用、長碳鏈脂肪酸代謝、活性氧類(ROS)代謝等。細胞中過氧化氫體生合成蛋白(Peroxisomal biogenesis factor, Peroxins)負責過氧化氫體的增生及發育，主要的增生方式分成由 Pex3, Pex16, Pex19 為主的過氧化氫體新生合成(de novo synthesis)以及由 Pex11ß 為主的過氧化氫體分裂增生(Peroxisome fission) 這兩種方法。在實驗室先前的研究中發現，隨著肌肉生成過程，過氧化氫體的數量也會逐漸增加，暗示了肌肉生成過程與過氧化氫體之間的相互關係；而在癌症惡質症環境中，過氧化氫體相關基因也呈現下降的趨勢。因此，本篇便著重探討過氧化氫體於肌肉生成及癌症惡質症之間的關聯性。實驗中我們發現，在肌肉生成過程中，不論是 in vivo 或 in vitro，過氧化氫體相關基因的表現皆呈現逐漸上升的趨勢，且過氧化氫體的新生數量也逐漸增加。同時觀察到，MRFs(Myogenic regulatory factor)會直接對 Pex3, Pex16, Pex19 啟動子進行調控。而上述實驗結果指出，Pex3 在肌肉生成過程中似乎扮演著很重要的角色。在藉由 knockdown Pex3 的細胞株中觀察到，大部分大量表現 Pex3 細胞株中觀察到除了過氧化氫體數量及形態上的改變，過氧化氫體及粒線體的功能並沒有太大的改變，然而在大量表現 Pex3 後細胞的分化效率卻有顯著地下降，指出在肌肉中，Pex3 對於過氧化氫體及粒線體扮演著舉足輕重的角色，並且在肌肉分化過程需要被精準地調控。此外，在經過有氧呼吸運動訓練後發現，快縮肌與慢縮肌之間過氧化氫體新生合成因子表現方式不同，並且觀察到在肌肉中過氧化氫酶並不位於過氧化氫體內。在早發性癌症惡病質小鼠內，觀察到在快縮肌內 Pex16 及 Acox1 異常上升，同時藉由 RNAseq 分析發現在晚發性小鼠快縮肌可以觀察到過氧化氫體相關基因大量被影響。此外，早發性與晚發性小鼠之間，大部分的 MRFs 表現趨勢類似，唯獨 MyoG 在早發性小鼠中出現異常上升，並且在快縮肌組別中出現較嚴重的症狀。將大量表現 MyoG 細胞株培養於癌症惡質症的環境中觀察到，兩者的加成性會影響肌肉分化並導致肌肉萎縮，造成癌症惡質症的惡化。;Peroxisome is an important organelle for cell metabolism, including reducing ROS(Reactive oxygen species), very long-chain fatty acid, lipid metabolism, and so on.Peroxisomal biogenesis factors (Peroxin) are involved in several procedures of peroxisome biogenesis, and in the two major ways regulating the number of peroxisomes, de novo synthesis is regulated by Pex3, Pex16, and Pex19 while growth and division is mainly regulated by Pex11β. As the number of peroxisomes has been found to be increased during myogenesis in our previous study, therefore, in this thesis, I want to clarify how the peroxisome is regulated in myogenesis and cancer cachexia. Here I found the expression of many peroxisome related genes is increased during myogenesis both in vitro and in vivo. Meanwhile, MRFs (Myogenic regulatary factors) show their ability to regulate Pex3, Pex16, Pex19 promoters derectly. These data all points out that Pex3 plays an important role in myogenesis. In Pex3 knockdowned cells, neither peroxisome nor mitochondria was functioning properly, and the number and morphology of both organelles were changed significantly. Furthermore, less total and tubular shape peroxisomes were observed in these cells. On the other hand, in Pex3 over-expressed cells, the number of peroxisome was increased, and more tubular shape peroxisomes were found. However, the function of peroxisome and mitochondria were both the same as that in controll cells. However, over-expression of Pex3 lead to poorer myogenesis, indicating that Pex3 level is critically regulated during myogenesis. Interestingly, after aerobic exercise training, peroxisome related genes were differentially regulated in different muscle types, the expression level of Pgc1α is similar to Pex19 level but not Pex3. We were also surprised to find the location of Catalase out of peroxisome in myofibers in vivo. In Cancer cachexia, the expression of Pex16 and Acox1 was abnormally increased in fast-twitch SKM. With RNAseq analysis, the peroxisome related genes were found significantly regulated in fast-twitch SKM of late onset mice. Meanwhile, MRFs were mostly the same in both early onset and late onset groups, but only MyoG was abnormally absent in fast-twitch SKM of early onset group. In MyoG over-expressed cells, myogenesis was functionally normal, but serious muscle atrophy and myogenesis dysfunction were observed when MyoG and cachexia signals were combined.
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