生物現象是動態，交互影響的複雜系統。去神經化導致的肌肉萎縮，往往造成不可逆永久傷害(如外傷性脊髓傷害與蘿蔔腿小腿神經阻斷術等) ，或是可逆短暫肌肉萎縮(如肉毒桿菌素注射)。目前除了治療效果面臨瓶頸，機制亦存在許多未解之謎。本研究比較動物實驗兩種去神經化(肉毒桿菌素注射與切神經)長時間(一年)機制之後，除了發現肉毒桿菌素注射的效果與頻率與劑量相關，長期而言還會造成肌肉重量與表面型態[不完全]恢復，這和過去文獻的結論大相逕庭之外; 肉毒桿菌素注射亦比切神經在所有訊息傳導表現較弱，尤其細胞凋亡表現上，有較弱與不持久的細胞凋亡誘發因子(硫胱氨酸蛋白酶-獨立細胞凋亡路徑)。並且，動物實驗的肌肉重量分析與本研究所收集的人類臨床兩種去神經化治療的數據，相吻合一致。選擇性肉毒桿菌素注射與切斷單一肌肉神經的實驗設計，發現代償性肌肉現象，讓肌肉功能迅速恢復至正常的水平，可供臨床上釐清患者對於療程是否會造成肢體失能的恐懼與疑慮。再者，去神經化的存活，細胞凋亡訊息傳導，肌纖維表面複雜度動態長期時間序表現模式，呈現高度的同時與雙相性，也就是逐漸增加到一個時間點後，再逐步下降 (切神經與肉毒桿菌素的高峰時間點分別為第8與4週)，這也和過去的短期去神經化文獻研究結論不同。發現去神經化的模式之後，接著，本研究冀望探討扮演與細胞外間質，產生內外雙向聯繫，位置與肌肉收縮傳達有關的整合素，來分析去神經化動態變化是否與整合素高度相關。研究結果確認，與存活訊息相關的整合素與其下游訊息傳導分子也驚人呈現同時，雙相模式。此外，利用電子顯微鏡分析肌纖維內部與表面顯微構造，除了內部構造切神經與肉毒桿菌素分別呈現不可逆與可逆構造崩壞，排列失序的變化之外; 整合素表現量會與肌纖維的表面複雜度成高度正相關。此發現可以協助未來研究組織變化時，簡化觀察複雜訊息系統的窗口。總之，本研究藉由建立動物實驗模式，加上作者近年來蘿蔔腿小腿神經整形手術的經驗，建立更清晰的肌肉動態圖像，同時對於臨床運用與解讀更有益處。

Biosystem is a dynamic, complex and interconnected system. Neurectomy and BoNT-A injection have been found in clinical practice to decrease skeletal muscle mass or activity. The treatment principles for nerve injuries have remained little changed for decades despite major advances in understanding. Comparing both denervated groups, the BoNT-A injection whose effect depends on the dose and frequency, not only induces incomplete long-term muscle weight recovery, but shows not long-lasting AIF mediated caspase-independent apoptosis. Both denervated groups show rapid functional recovery due to the muscle compensation and delicate experimental design by selective neurectomy. Molecular expressions (survival and apoptosis) and surface complexities of myofibers on both denervation procedures demonstrate the coherent and biphasic pattern: initial increase, later decay. The peak on the BoNT-A and neurectomy group is 4 and 8 weeks after denervation respectively. Furthermore, the research verifies that the tissue surface reacts accordingly when biochemical responses change. The inner microscopic structures examined by the transmission electron microscope show the irreversible and reversible alterations including sarcomere disarrangement. The integrin and its downstream signaling molecules (Ras/Raf/Erk1/2, MHC, actin and RhoA) correlate with the survival signaling pathway. The surface textures examined and quantified by the scanning electron microscope are highly correlated with the integrin expressions (CAM-ECM interplay, correlation coefficient r=0.873). The study compares the differences between the BoNT-A injection and neurectomy, and establishes the dynamic pattern of specific mechanism based on in vivo experimental model and human calf surgery experiences.

誌謝 i
縮寫表 (Abbreviations) ii
中文摘要 (Abstract in Chinese) v
英文摘要 (Abstract in English) vi
第一章 緒論 (Introduction) 1
第二章 研究方法與材料 (Materials and Methods) 9
第三章 實驗結果 (Results) 15
第四章 討論 (Discussion) 21
第五章 結論與展望 (Conclusion and Perspectives) 50
第六章 參考文獻 (References) 52
第七章 圖表 (Tables and Figures) 66
附錄 (Appendices) 88

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