根據歐洲肌少症聯盟（European Working Group on Sarcopenia in Older People, EWGSOP），肌少症為「隨年紀增加而流失的肌肉質量和功能下降」。2015年內政部統計，我國65歲以上長者，肌少症盛行率約9％，平均每10名老年人就有1人患有肌少症；80歲以上高齡長者，肌少症盛行率更增至15％，每7人就有1人患有肌少症。目前已知罹患肌少症可能造成疾病發生率提高、生活品質降低、甚至死亡，然而卻沒有有效治療肌少症的方法。兒茶素又稱為茶多酚，為茶葉中黃烷醇類總稱，主要為多種化合組成，其中以(-) –Epigallocatechin-3-gallate (EGCG)為綠茶萃取物中含量最高成分，先前本實驗室發現，在40週齡SAMP8(senescence-accelerated mouse prone 8)小鼠的肌肉組織中，Akt活性及GLUT4表達降低，推斷SAMP8小鼠的肌肉有胰島素抗性。而餵食SAMP8小鼠每公斤含有3.2g EGCG飼料，可增加肌肉組織中Akt活性、提高GLUT4表達以及活化AMPK，進而降低血糖與胰島素。Akt透過調控mTOR/p70s6k 與FoxO- MuRF-1/Atrogin-1訊息路徑，是骨骼肌蛋白質合成與降解的重要調節因子。因此，本研究利用老化促進鼠SAMP8來探討EGCG是否會能緩解老化導致的肌肉質量流失進而改善肌少症。首先我們利用SAMP8小鼠建立肌少症實驗動物模式，觀察12、24、32、40週齡之SAMP8小鼠，發現SAMP8小鼠之四肢握力由12週齡持續增加至32週齡開始顯著下降，然而肌肉質量在40週齡時則顯著降低。上述結果得知，SAMP8小鼠在32週齡可定義為肌少症前期(pre-sarcopenia)，直到40週齡即為肌少症(sarcopenia)。接著，將SAMP8分為一般飼料組及餵食EGCG組(每公斤飼料含3.2公克EGCG) 。其中餵食EGCG組又分為預防組(由24週餵養至40週)及治療組(由32週餵養至40週)，並以SAMR1作為對照組。結果顯示，餵食EGCG可以有效提升SAMP8小鼠四肢握力強度、肌肉質量及肌肉纖維截面積，因此，給予EGCG皆可預防及改善肌肉流失。進一步探討其分子機制發現，EGCG可以增加AKT/mTOR/p70s6k訊息路徑以增加蛋白質合成，並減低FoxO入核以降低肌肉萎縮基因MuRF-1和Atrogin-1表達來降低泛素蛋白酶體系統(Ubiquitin-proteasome system)的蛋白質降解。EGCG亦透過活化mTOR訊息傳導路徑調控細胞自噬(Autophagy)，mTOR活化亦可抑制自噬體膜形成所需的相關蛋白Atg13，Atg13是決定啟動自噬作用與否的重要蛋白，EGCG可以抑制Atg13蛋白表達進而再藉由抑制LC3及P62活性來減少自噬作用的發生。本研究進一步利用老化促進鼠SAMP8探討老化過程中，粒線體的動態平衡在綠茶多酚EGCG改善肌少症的角色。結果顯示在給予EGCG後可以有效改善兩組SAMP8小鼠粒線體融合(Mfn1、Mfn2與OPA1)及粒線體分裂(Drp1、Fis1與Mff1)的相關基因表達，進而維持細胞內粒線體動態平衡，由研究結果得知老化肌肉中粒線體動態平衡的機制改變主要是造成老化引起的粒線體功能失調。研究發現老化促進小鼠(SAMP8)可作為肌少症研究的動物模式。餵食EGCG可以有效改善老化促進小鼠粒線體動態平衡的相關基因表達，藉由降低「自噬-溶酶體系統」和「泛素-蛋白酶體途徑」的活化延緩蛋白降解。此外，餵食EGCG也藉由活化Akt/mTOR途徑促進蛋白質合成。本研究結果推論，EGCG減緩老化時期肌肉蛋白降解是透過改變粒線體融合與分裂的平衡以及自噬流通改善粒線體品質控管，因而可能進一步提升粒線體的功能及活性來延長粒線體壽命，從而增加骨骼肌蛋白質合成和減少蛋白質降解，並延緩老化而有效改善肌少症。

SUMMARY
The purpose of this study was to investigate the efficacy of EGCG on age-associated skeletal muscle atrophy in Senescence-accelerated mouse (SAM) prone 8 (SAMP8). SAMP8 shortens the process of aging and may facilitate an alternative model for studying aging-related sarcopenia. (-) –Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, has been shown to improve muscle function in a mouse model of muscular dystrophy and to attenuate atrophy in cancer cachexia. In present study, molecular mechanism of aging-related skeletal muscle atrophy in SAMP8 model of sarcopenia established by our laboratory at aged 12, 24, 32, and 40 weeks was investigated. Results showed that the peaks of muscle mass and muscle strength were observed at aged 32 weeks and the declines of that were observed at aged 40 weeks. Therefore, 32-week-old SAMP8 mice were fed with control diet or control plus 0.32 % of EGCG diet for 8 weeks. SAMP8 supplemented with EGCG had significantly greater gastrocnemius muscle mass, fiber cross-sectional areas and muscle strength than that of SAMP8 without EGCG supplement. In addition, EGCG ameliorated both muscle-specific E3 ubiquitin ligase including MuRF-1 and Atrogin-1 and mitochondrial dynamics fusion and fission, which contribute to the inhibiting autophagy evidenced in SAMP8 mice.In summary, mitochondrial quality control is an unique target for sarcopenia therapy due to it dysfunction as a primary instigator of sarcopenia. EGCG supplement acts on mitochondrial quality control via restoring mitochondrial biogenesis, mitochondrial fusion and fission, and autophagic flux, thus contributing to balance of skeletal muscle protein synthesis and degradation.

Keyword: EGCG, Sarcopenia, Aging, SAMP8 mice

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