根據臨床症狀及過去文獻指出，糖尿病會伴隨著肌肉萎縮，主要因素為胰島素阻抗活化蛋白質分解或導致脂質浸潤，致使糖尿病患者肌力退化，甚至影響行動能力。Oligonol 是一種以荔枝果實為原料，經特殊製成的寡分子多酚，與catechin形成穩定且容易吸收之結構。先前文獻指出，Oligonol具有抗發炎、抗氧化以及調節脂肪代謝之功效。本研究利用糖尿病老鼠db/db來探討Oligonol是否能緩解肌肉萎縮。實驗組為m/m、db/db與db/db老鼠分別餵食Oligonol低劑量( 20 mg/kg )、高劑量( 200 mg/kg ) 十週，犧牲後取老鼠的脛骨前肌與腓腸肌進行組織切片，並探討肌肉萎縮和脂質浸潤相關之分子機制。結果顯示，餵食Oligonol不會影響db/db老鼠體重，然而於血糖值、胰島素與葡萄糖耐受性結果發現，20 mg/kg Oligonol能夠降低糖尿病之高血糖及高胰島素情形，亦可促進db/db老鼠對血液中葡萄糖清除能力，增進胰島素之敏感性。再者，Oligonol減少db/db老鼠Adipokines ( Resistin以及IL-6) 濃度。進一步觀察脛骨前肌HE染色切片發現，db/db老鼠肌肉截面積縮小，相反地，餵食Oligonol十週後，低高劑量皆可預防肌肉流失。此外，Oligonol會降低肌肉萎縮基因MuRF1及Atrogin-1之表現量。更進一步探討其轉錄因子活性發現，Oligonol活化Sirt1，進而抑制轉錄因子Foxo活性來減緩肌肉蛋白質分解，亦會抑制轉錄因子NFκB進入細胞核內活化下游萎縮基因。更深入以Luciferase assay探討MuRF1 promoter 活性發現，Oligonol 能抑制MuRF1 promoter 活性來減緩肌肉萎縮。Oil red 染色結果顯示油滴堆積於db/db老鼠肌肉束中，而Oligonol會藉由活化AMPK及pparα 促進脂質分解，進而有效減少油滴累積，緩解脂質浸潤。總結以上結果，Oligonol改善糖尿病所引起的肌肉萎縮及脂質浸潤。另以細胞模式實驗，給予C2C12肌肉纖維母細胞預處理Oligonol 10、25、50 μg/ml，再添加棕梠油酸模擬胰島素阻抗之環境，發現棕梠油酸組有提前衰老以及細胞週期停滯現象，進而抑制肌肉細胞發育。而Oligonol組卻可以有效預防這些現象產生，並且保護肌肉發育之過程。綜合以上結果，推論Oligonol可作為糖尿病病患改善肌肉相關併發症之膳食補充品。

SUMMARY
The purpose of this study was to examine whether oligonol ameliorates muscle atrophy in db/db mice and palmitate-induced premature in C2C12 myoblast. Oligomol, a flavonoid-rich leechy fruit extract, has been known for anti-inflammatory and anti-cancer properties. In this study, we investigated its effect on diabetes-induced muscle atrophy. Male db/db mice were fed with regular diet and supplemented with 20 and 200 mg/kg oligonol for ten weeks. Oligonol protected db/db mice against decreased muscle cross-section area. In addition, Up-regulated both muscle-specific E3 ubiquitin ligase including MuRF1 and Atrogin-1 in db/db mice were reversed by oligonol. These changes were accompanied by reduction of nuclear transcription factor, NFκB and Foxo3a. Moreover, oligonol supplementation diminished fat infiltration in db/db mice by activation of AMPK and pparα gene expression. In vitro, Oligonol protected C2C12 myblast from palmitate-induced cell cycle arrest, premature and inhibition of myblast differentiation. Overall, oligonol may be a dietary supplement to improve diabetes-induced muscle atrophy and palmitate-induced premature in C2C12 myoblast.

Keyword: Diabetes, Muscle atrophy, Oligonol

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