肌少症是指隨著年齡增長或因其他因素，如飲食不當或疾病等導致骨骼肌質量與強度下降的綜合症候。本實驗室先前探討各種植化素對於肌肉萎縮的研究發現，荔枝小分子寡酚（oligonol）與兒茶素（Epigallocatechin gallate, EGCG）可延緩老化肌肉萎縮以及香椿葉能促進葡萄糖進入肌肉細胞的利用，進而降低血糖及減緩胰島素抗性的效果，合作實驗室也證實蘆筍莖萃取物（A Standardized Extract of Asparagus officinalis Stem, ETAS®）可改善老化認知功能。本研究實驗一延續先前本實驗室在SAMP8肌少症模式中24週齡SAMP8小鼠肌肉功能下降的結果，繼續探討ETAS®是否能延緩老化造成肌肉功能開始下降及其相關機制。本研究室長期研究香椿葉功效，然而香椿其他部位如香椿果實、樹皮之功效尚未探討，文獻顯示，香椿果實與樹皮具有降低肝臟細胞之游離脂肪酸的脂質合成，然而對高脂飼料在肌肉功能下降與相關機制的研究尚付闕如，因此本研究實驗二主要目的是探討香椿果實與樹皮對餵食高脂飼料小鼠之肌肉的影響。

實驗一 蘆筍萃莖取物ETAS®減緩老化促進老鼠之肌握力及機制研究
實驗一探討蘆筍莖萃取物（A Standardized Extract of Asparagus officinalis Stem, ETAS®）改善老化相關肌少症之功效及其分子機轉。蘆筍富含胺基酸、蘆丁、皂苷和酚類化合物等成分，ETAS®乃利用蘆筍的莖為原料經發酵後萃取而得，其成分以羥甲基糠醛（5‑Hydroxymethyl-2-furfural, HMF）衍生物為主，已被證實具有調節晝夜節律訊息因子及改善認知之效益。本研究利用12週齡老化促進小鼠（Senescence-Accelerated Mouse, SAMP/Ta Slc）分為正控制組為SAMR1（SAM resistant 1）、負控制組為SAMP8（SAM prone 8）以及SAMP8餵食ETAS®（100 mg/k.g.w及500 mg/k.g.w）12週之實驗組，24週齡測量握力後犧牲，取小鼠的腓腸肌萃取蛋白質和核醣核酸進行相關指標的偵測。結果顯示，24週齡SAMP8小鼠的四肢握力顯著低於SAMR1組，餵食ETAS®顯著提升SAMP8小鼠的握力。進一步探討分子機制，本研究發現 ETAS®可透過活化AKT /mTOR /p70S6K訊息途徑增加肌肉蛋白合成（protein synthesis），並抑制NFB進入細胞核，降低MuRF1與Atrogin-1 蛋白質表現，減緩肌肉通過泛素-蛋白酶體（ubiquitin-proteasome system）所造成的蛋白質降解（protein degradation）。ETAS®同時會降低Atg13、LC3、p62與自噬作用相關的蛋白表達，減緩自噬-溶酶體系統（autophagy-lysosome system）所介導的肌肉蛋白質降解。另外ETAS®可以降低肌肉中肌肉抑制素（Myostatin）的蛋白質表達量可降低肌肉的蛋白質降解。本研究也發現，24週齡SAMP8小鼠骨骼肌中負責調控粒線體生合成與融合/分裂基因，相較於SAMR1顯著降低。餵食ETAS®可以提高粒線體生合成相關基因（PGC1α、Tfam、Ndufs8）與融合相關基因（Mfn1、Mfn2、Opa1）表達及裂變相關基因（Drp1、Fis1、Mff1），進而提昇粒線體生合成與融合之能力。此外本研究發現ETAS®可以增加SAMP8小鼠骨骼肌中粒線體PINK1蛋白質的表達量。總結以上，ETAS®會增加骨骼肌蛋白質合成並降低蛋白質降解，改善粒線體生合成及融合指標，並下調與細胞自噬相關訊息因子。本研究結果顯示，ETAS®可改善因老化引起的肌肉萎縮，未來可能可以提供年長者作為延緩肌肉萎縮的膳食補充品使用。

實驗二 香椿果實及樹皮預防高脂飼料小鼠之肌握力及機制研究
過去研究發現，高脂飲食不但導致胰島素的抗性，且會增加肌肉萎縮。綜合本研究室多年的實驗結果顯示，香椿葉萃取物具抗氧化能力，可保護肝臟細胞、緩解脂肪肝、減少體脂肪堆積、降低血糖及胰島素抗性，並能促進肌肉細胞對葡萄糖的利用，但香椿果實跟樹皮萃取物相關的研究甚少，對餵食高脂飼料小鼠肌肉影響則尚不清楚。本研究將5週齡C57BL/6小鼠隨機分組，分為控制組（一般飲食）、高脂飲食（40%脂肪）、香椿果實萃取物+高脂飼料、香椿樹皮萃取物+高脂飼料。實驗中香椿組先分別管餵香椿萃取物4週，之後同時給予高脂飼料讓小鼠自由攝食持續25週，小鼠三十三週齡時測量握力，三十四週齡犧牲後取其兩側腓腸肌，進行相關蛋白質與核醣核酸的分析。結果顯示，高脂飲食組的握力顯著低於一般飲食組，餵食香椿果實及香椿樹皮萃取物組可顯著提升小鼠握力及腓腸肌重量。因此針對香椿果實及樹皮萃取物提升小鼠握力的分子機制探討發現，餵食香椿果實及樹皮萃取物可透過活化AKT /mTOR /p70S6K訊息途徑增加肌肉蛋白合成（protein synthesis），並抑制NFB、FoxO1a進入細胞核，降低MuRF1與Atrogin-1蛋白質表現量，減緩肌肉通過泛素-蛋白酶體 （ubiquitin-proteasome system）所造成的蛋白質降解（protein degradation）。餵食香椿果實及樹皮萃取物也會降低Atg13、 LC3、p62等自噬作用相關蛋白的表達，減緩自噬-溶酶體系統（autophagy-lysosome system）所介導的肌肉蛋白降解。另外ETAS®可以降低肌肉中肌肉抑制素（Myostatin）的蛋白質表達量可降低肌肉的蛋白質降解。餵食香椿可以提高粒線體生合成相關基因（PGC1α、Tfam、Ndufs8）與融合相關基因（Mfn1、Mfn2、Opa1）表達及裂變相關基因（Drp1、Fis1、Mff1），進而提昇粒線體生合成與融合之能力。此外本研究發現香椿果實及樹皮萃取物可以預防進而增加高脂飲食小鼠骨骼肌中粒線體PINK1蛋白質的表達量。總結以上結果，香椿果實及樹皮可以增加骨骼肌蛋白質合成並降低蛋白質降解，減緩肌握力。本研究建議香椿果實及樹皮可作為改善高脂飲食引起肌握力下降之膳食補充品。

實驗一關鍵字: 蘆筍莖萃取物（ETAS®）、肌握力、細胞自噬

實驗二關鍵字: 香椿果實及香椿樹皮萃取物、肌肉握力、細胞自噬

Experiment one: Study of A standardized extract of Asparagus officinalis stem（ETAS®）on the muscle strength and mechanism in senescence-accelerated mouse P8
SUMMARY
The purpose of this study was to examine whether ETAS® ameliorates aged-related muscle atrophy in Senescence-accelerated mouse （SAM） prone 8 （SAMP8）. ETAS®, a standardized extract of Asparagus officinalis stem, consists of 5-hydroxymethyl-2-furfural （HMF）, has been found to ameliorate cognitive impairment and normalize circadian rhythm signaling in senescence-accelerated mice prone 8 （SAMP/Ta Slc）. Sarcopenia is an aging-related symptom with a significant reduction in mass and strength of skeletal muscle. In this study, we investigated the effect of ETAS® on aging-related muscle atrophy and its related signaling. SAMP8 and senescence accelerated mouse resistant 1 （SAMR1） are recognized as appropriate models for studying muscle aging. We used SAMR1 as positive control, SAMP8 as negative control and SAMP8 + ETAS® as experimental group. Male SAMP8 mice were fed with regular diet supplemented with 100/500 mg/kg ETAS® for 12 weeks. Dietary supplement of ETAS®for 12 weeks led to increase grip strength. ETAS® supplementation significantly up-regulated protein synthesis via phosphorylation of AKT/mTOR /p70S6K in SAMP8 mice. ETAS® prevented nuclear translocation of NFκB and FoxO1a, thereby suppressing Atrogin-1 and MuRF1 expression. ETAS® inhibited autophagy by decreasing the levels of Atg13, LC3 and p62. In addition, ETAS® downregulated myostatin of gastrocnemius in SAMP8. ETAS® upregulated mitochondrial fusion-related gene （Mfn1、Mfn2、Opa1） and fssion-related gene （Drp1、Fis1、Mff1） or biogenesis-related gene （PGC1α、Tfam、Ndufs8）, additionally ETAS® upregulated PINK1 protein of protein level in SAMP8 gastrocnemius, which contribute to the inhibiting autophagy in SAMP8 mice. In conclusions, our results suggest ETAS® as a supplement for alleviating muscle strength by improving protein synthesis via phosphorylation of AKT/mTOR /p70S6K pathway, suppressing protein degradation via ubiquitin-proteasome and the autophagy-lysosome systems or downregulated level of myostatin, ameliorated mitochondrial dynamics and biogenesis in SAMP8 mice.
Keywords: SAMP8 mice, Muscle grip strength, ETAS®

Experiment two: Study of Toona sinensis on the muscle strength and mechanism in high fat diet-fed mice
SUMMARY
Studies have been demonstrated that high-fat diet intake leads to insulin resistance and causes muscle atrophy. Previous findings from our laboratory have shown that Toona sinensis leaves (TSL) extract protect liver from oxidative stress-induced damage and ameliorate obesity-induced steatosis, body fat accumulation, and blood sugar increase as well as alleviate insulin resistance and glucose uptake. However, little is known about Toona sinensis fruit (TSF) and bark (TSB), especially on high-fat diet (HFD)-fed mice muscle. Continuous high caloric intake can lead to negative health condition, such as obesity, hypertension, hyperlipidemia, and so on. The purpose of this study was to examine whether TSF and TSB prevent high-fat diet-induced muscle atrophy in C57BL/6 mice. Five-week old male C57BL/6 mice were assigned randomly to control group (fed with normal diet), HFD (fed with 40% fat) group, TSF extracts + HFD group and TSB extracts + HFD group. The mice in TSF and TSB groups were fed with normal diet and gave them oral gavage for four weeks. After four-week treatment with TSF and TSB, mice were continuously giving oral gavage with HFD. Mice in HFD and control groups were also treated with HFD and normal diet for additional 25 weeks, respectively. The grip strength were measured on thirty three-week old mice. Thirty four-week old mice were sacrificed and collected the gastrocnemius to analyze the related protein and ribonucleic acid expressions. The grip strength and muscle weight in HFD group was significantly lower than control group. The grip strength and muscle weight of mice treated with TSF or TSB was significantly higher than HFD group. To further investigate the molecular mechanism of TSF and TSB-improved muscle function, we found that TSF and TSB increase protein synthesis via phosphorylation of mTOR, AKT, and p70S6K in HFD-fed mice. Moreover, TSF and TSB prevent nuclear translocation of NFκB and FoxO1a as well as myostatin thereby suppressing Atrogin-1 and MuRF1 expression. TSF and TSB inhibit autophagy by decreasing the levels of Atg13, LC3 and p62. Additionally, the mitochondrial fusion-related gene (Mfn1, Mfn2 and Opa1) and fssion-related gene (Drp1、Fis1、Mff1) or biogenesis-related gene (PGC1, Tfam and Ndufs8) and PINK1 protein were all upregulated in mice fed with TSF and/or TSB. In conclusions, our results suggest that TSF and TSB may use as a daily supplement for alleviating obesity-induced sarcopenia in mammals. In conclusions, our results suggest TSF and TSB as a supplement for alleviating obesity-induced sarcopenia by increasing protein synthesis via phosphorylation of AKT/mTOR /p70S6K pathways, suppressing protein degradation via ubiquitin-proteasome and the autophagy-lysosome systems, or ameliorated mitochondrial dynamics and biogenesis in high fat diet-fed mice.
Keywords: C57BL/6 mice, Muscle grip strength, High fat diet, Toona sinensis fruit and bark

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