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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 姜至剛(Chih-Kang Chiang) | |
| dc.contributor.author | Hao-Chun Chuang | en |
| dc.contributor.author | 莊皓淳 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:26:56Z | - |
| dc.date.available | 2021-08-31 | |
| dc.date.available | 2022-11-24T03:26:56Z | - |
| dc.date.copyright | 2021-08-31 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-20 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81029 | - |
| dc.description.abstract | "全球正面臨人口老化的危機，伴隨而來的健康風險急劇攀升，而患有「肌少症」的年長者更被視為首當其衝的議題。肌少症為肌肉在質量、力量與功能方面的降低與不全，常源自於年齡增長、慢性疾病以及發炎反應等。先前已有研究指出促發炎細胞激素，如tumor necrosis factor alpha (TNF-α)、糖皮質激素，如dexamethasone (DEX)以及尿毒素，如indoxyl sulfate (IS)均會促使肌少症的發生。此外，肌少症患者常出現肌肉再生能力減損與肌肉纖維化的情形，其中，transforming growth factor beta (TGF-β) 是廣為人知的促纖維化因子，能抑制肌肉生成(myogenesis)，而肌肉為全身最大器官之一，可受其他全身性因子影響。近來胞外小體(extracellular vesicles, EVs)研究顯示，由肌肉所分泌出之EVs能夠於自身或至其他器官產生自分泌或旁分泌之交互作用。為探討肌少症誘發之總體調控因子，本實驗室過去研究發現C2C12肌纖維母細胞暴露於TGF-β1下所分泌出的分化胞外體不利於肌肉之分化，更進一步在TGF-β1之分化胞外體中發現微小核醣核酸(microRNA, miRNA)有所變化，其中，對肌肉具有專一性且已知的myomiR，如miR-1、 miR-133、206之表現量降低；此外，尚有新發現之miR-532-3P 表現亦下降，然而仍未知曉其功能。因此，本篇研究欲探討miR-532-3P在骨骼肌生成的過程中所扮演的角色與調控機轉，並模擬於TGF-β1之分化胞外體中其缺乏的現象，進而釐清miR-532-3P 對骨骼肌之影響。首先，於老化導致活動力下降之小鼠與肥胖模式之糖尿病小鼠合併肌肉耗損之骨骼肌中，我們發現伴隨TGF-β1含量增加，miR-532-3P之表現量減少；再者，於細胞實驗中，由myosin heavy chain (MyH)蛋白表現而論，不管TGF-β1或IS 皆會抑制肌肉分化，而TNF-α 則會促進肌肉降解，令人感興趣的是內源性miR-532-3P之含量皆一致性的減少。為了確立miR-532-3P對肌纖維母細胞增生之作用，當抑制內源性miR-532-3P時並不會影響肌纖維母細胞的增生；其次，當肌纖維母細胞分化時，抑制miR-532-3P將導致分化不佳，並弱化分化指標，如MyoD (myoblast determination protein 1)、MyoG (myogenin)、MyH蛋白表現降低，使肌小管(myotube)生成減少；接著，經由miRNA序列作用標的預測，我們提出分化不良可能與small ubiquitin-related modifier 1 (SUMO1)和terminal nucleotidyltransferase 4B (TENT4B)表現增加具有關聯性，但詳細機轉尚待更深入的探討。另一方面，儘管抑制miR-532-3P不會促進已分化之肌小管萎縮，然而，大量表達miR-532-3P卻能挽救DEX誘發之肌肉萎縮。最後，於甘油誘導肌肉損傷與再生之動物模式中，發現內源性miR-532-3P含量隨之增加。綜合而論，miR-532-3P在骨骼肌中扮演著有益於肌生成之myomiR的角色。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:26:56Z (GMT). No. of bitstreams: 1 U0001-1808202117180400.pdf: 4878013 bytes, checksum: 3bde3582767a6b3989c1308526e370e4 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "口試委員會審定書 I 致謝 II 中文摘要 IV Abstract VI List of abbreviations VIII Contents XI Chapter 1 Introduction 1 1.1 Aging worldwide 1 1.2 Sarcopenia 2 1.3 Skeletal muscle myogenesis 5 1.4 Anabolic and catabolic signaling pathways in skeletal muscles 6 1.4.1 Small ubiquitin-related modifier 8 1.5 MicroRNAs 10 1.6 Extracellular vesicles 12 1.7 Transforming growth factor β 15 1.8 Indoxyl sulfate 18 1.9 Tumor necrosis factor alpha 19 Chapter 2 Aims 22 Chapter 3 Materials and Methods 23 3.1 Cell culture and treatments 23 3.2 Animal model 23 3.2.1 Glycerol-induced muscle injury and muscle regeneration 23 3.2.2 Senile mice 24 3.2.3 Diabetic nephropathy-related sarcopenia 24 3.3 Transfection 25 3.4 RNA extraction, reverse transcription, and quantitative real-time PCR 26 3.5 Protein extraction and immunoblotting 28 3.6 Assessment of cell proliferation 29 3.7 Cell cycle analysis and flow cytometry 30 3.8 Construct of SUMO1-3’-UTR 30 3.9 Dual luciferase reporter assay 31 3.10 Morphological analysis 32 3.10.1 Hematoxylin and eosin staining 32 3.10.2 Masson's trichrome staining 33 3.11 Statistical Analysis 34 Chapter 4 Results 35 4.1 MiR-532-3P is reduced in skeletal muscles of aged and db/db mice 35 4.2 MiR-532-3P is downregulated in impaired myogenic differentiation and enhanced muscle degradation in vitro models. 36 4.3 Knockdown of miR-532-3P cannot thoroughly suppress myoblast proliferation. 37 4.4 Inhibition of miR-532-3P jeopardizes myogenic differentiation. 38 4.5 SUMO1 is the potential target of TGF-β1-mediated miR-532-3P during myogenic differentiation. 39 4.6 TENT4B is the probable target of TGF-β1-mediated miR-532-3P during myogenic differentiation. 40 4.7 Repression of miR-532-3P cannot give rise to muscle atrophy of the well-differentiated myotubes. 41 4.8 Overexpression of miR-532-3P reverses dexamethasone-induced muscle atrophy. 41 4.9 MiR-532-3P is upregulated during muscle regeneration. 42 Chapter 5 Discussion 44 Chapter 6 Conclusion 51 Chapter 7 Future perspectives 52 7.1 MiR-532-3P inhibition or mimicry in vivo 52 7.2 Clinical specimen of miR-532-3P among sarcopenia individuals 52 Chapter 8 References 54 Chapter 9 Figures 66 Figure 1 66 Figure 2 67 Figure 3 68 Figure 4 71 Figure 5 75 Figure 6 78 Figure 7 82 Figure 8 85 Figure 9 87 Figure 10 90 Figure 11 92 Chapter 10 Supplementary Figures 93 Supplementary Figure 1 93 Supplementary Figure 2 96 Supplementary Figure 3 99" | |
| dc.language.iso | en | |
| dc.subject | 再生 | zh_TW |
| dc.subject | 肌少症 | zh_TW |
| dc.subject | 微小核醣核酸 | zh_TW |
| dc.subject | 肌肉生成 | zh_TW |
| dc.subject | 萎縮 | zh_TW |
| dc.subject | microRNA | en |
| dc.subject | regeneration | en |
| dc.subject | atrophy | en |
| dc.subject | myogenesis | en |
| dc.subject | sarcopenia | en |
| dc.title | MiR-532-3P在肌肉生成的過程中所扮演的角色 | zh_TW |
| dc.title | The role of microRNA-532-3P in myogenesis | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 劉興華(Hsin-Tsai Liu),洪冠予(Chih-Yang Tseng) | |
| dc.subject.keyword | 肌少症,微小核醣核酸,肌肉生成,萎縮,再生, | zh_TW |
| dc.subject.keyword | sarcopenia,microRNA,myogenesis,atrophy,regeneration, | en |
| dc.relation.page | 100 | |
| dc.identifier.doi | 10.6342/NTU202102485 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-20 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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