PI3K/Akt和AMPK信號通路在運動誘導(dǎo)的嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達中的作用

張云麗, 王 林, 劉鐵民

(聊城大學(xué)體育學(xué)院, 聊城 252059)

·綜 述·

PI3K/Akt和AMPK信號通路在運動誘導(dǎo)的嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達中的作用

張云麗, 王 林, 劉鐵民

(聊城大學(xué)體育學(xué)院, 聊城 252059)

骨骼肌在葡萄糖穩(wěn)態(tài)中扮演重要作用，葡萄糖轉(zhuǎn)運體4(glucose transporter 4，GLUT4)作為骨骼肌內(nèi)最主要的葡萄糖轉(zhuǎn)運蛋白，其轉(zhuǎn)位和表達的變化與胰島素抵抗的發(fā)生密切相關(guān)。本文綜述了近年來關(guān)于嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達的運動激活以及磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinases，PI3K)/蛋白激酶B(protein kinase B，Akt)和腺苷酸活化蛋白激酶(AMP-activated protein kinase，AMPK)信號通路介導(dǎo)運動改善骨骼肌葡萄糖攝取的研究進展，旨在為全面了解和明確運動影響嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達的機制。

骨骼肌; 運動; 胰島素抵抗; 葡萄糖轉(zhuǎn)運體4(GLUT4); 磷脂酰肌醇-3-激酶(PI3K);蛋白激酶B(Akt); 腺苷酸活化蛋白激酶(AMPK)

骨骼肌是代謝葡萄糖的重要外周組織，其葡萄糖代謝水平在調(diào)節(jié)全身血糖穩(wěn)態(tài)中發(fā)揮著重要作用。葡萄糖轉(zhuǎn)運體4(glucose transporter 4，GLUT4)是骨骼肌內(nèi)最重要的葡萄糖轉(zhuǎn)運蛋白，其介導(dǎo)的葡萄糖跨細胞膜的轉(zhuǎn)運是骨骼肌葡萄糖代謝的主要限速步驟，而GLUT4的轉(zhuǎn)位和表達的變化可以在一定程度上反映骨骼肌細胞的糖代謝狀況。關(guān)于GLUT4的轉(zhuǎn)位存在兩種不同刺激機制的假說, 胰島素刺激的GLUT4的轉(zhuǎn)位主要涉及磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinases，PI3K)/蛋白激酶B(protein kinase，Akt)(PI3K/Akt)信號通路, 而運動刺激的GLUT4的轉(zhuǎn)位主要涉及腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)信號通路[1,2]。

本文基于PI3K/Akt和AMPK信號通路存在復(fù)雜的交互作用以及運動對這兩種信號通路均可以發(fā)揮影響的理論作為依據(jù)，對運動刺激的嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達中PI3K/Akt和AMPK信號通路的作用進行探討，這對于了解胰島素抵抗相關(guān)疾病及評價運動對胰島素抵抗相關(guān)疾病的干預(yù)效果具有重要意義。

1 PI3K/Akt和AMPK信號通路與嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達

1.1 骨骼肌內(nèi)GLUT4的轉(zhuǎn)位和表達

GLUT4為跨膜轉(zhuǎn)運糖蛋白，相對分子質(zhì)量約為45 000～55 000，由12個跨膜片段(M1～M12)和1個位于N 端的胞外環(huán)狀結(jié)構(gòu)域組成。由GLUT4介導(dǎo)的葡萄糖攝取是骨骼肌利用葡萄糖的主要限速步驟，GLUT4的表達減少、轉(zhuǎn)位受阻及含GLUT4的囊泡不能與細胞膜融合或已融合但GLUT4活性降低等因素被認為是導(dǎo)致骨骼肌葡萄糖攝取缺陷，最終引起胰島素抵抗的主要因素[3,4]。有研究表明[5]，GLUT4基因敲除小鼠出現(xiàn)胰島素抵抗和葡萄糖耐受不良，靶向破壞肌肉的GLUT4, 引起GLUT4的蛋白表達減少，會使參與轉(zhuǎn)位的GLUT4的數(shù)量減少，導(dǎo)致骨骼肌細胞對葡萄糖的攝取與利用發(fā)生障礙，進而減弱胰島素信號轉(zhuǎn)導(dǎo)，并最終引起胰島素抵抗的發(fā)生。

骨骼肌細胞有一個復(fù)雜的膜系統(tǒng)，其中包括表面細胞膜和起源于橫小管的膜內(nèi)陷(T-小管)?；A(chǔ)狀態(tài)下，由于缺乏刺激，GLUT4主要儲存于細胞內(nèi)的囊泡，受刺激時這些囊泡轉(zhuǎn)位至質(zhì)膜系統(tǒng)，囊泡膜與質(zhì)膜發(fā)生融合，GLUT4插入質(zhì)膜以增加葡萄糖攝取[6-9]。對新生SD大鼠的骨骼肌細胞進行原代培養(yǎng)，結(jié)果表明胰島素和運動刺激通過不同的信號途徑促進骨骼肌細胞GLUT4轉(zhuǎn)位至質(zhì)膜[10]。

1.2 PI3K/Akt信號通路與骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達

胰島素刺激的骨骼肌內(nèi)GLUT4的轉(zhuǎn)位主要涉及PI3K/Akt信號通路。主要步驟如下: 胰島素與胰島素受體結(jié)合，繼而激活胰島素受體底物(insulin receptor substrate, IRS)和PI3K, 導(dǎo)致磷脂酰肌醇三磷酸(phosphatidylinositol 3-phosphate，PIP3)的產(chǎn)生;隨后PIP3分別與Akt和非典型蛋白激酶 C(atypical protein kinase C，aPKC)結(jié)合, 進而促使GLUT4轉(zhuǎn)位至表面細胞膜以攝取葡萄糖[1]。雖然IRS與PI3K的結(jié)合對于高脂飲食誘導(dǎo)的胰島素抵抗的SD大鼠骨骼肌內(nèi)GLUT4的轉(zhuǎn)位是必要的, 但是二者的結(jié)合還不足以刺激GLUT4介導(dǎo)的葡萄糖攝取的增加, 葡萄糖攝取的增加需要Akt的參與[11]。Akt是一種絲氨酸-蘇氨酸蛋白激酶, PIP3與Akt的PH結(jié)構(gòu)域結(jié)合, 促進Akt激活, 進而促進GLUT4的轉(zhuǎn)位和肌肉葡萄糖攝取[12]。有研究表明[9], Akt的激活可以促進骨骼肌內(nèi)GLUT4的轉(zhuǎn)位, 從而增加肌細胞的葡萄糖攝取。在胰島素刺激下, GLUT4從細胞內(nèi)囊泡向質(zhì)膜的轉(zhuǎn)位可以促進葡萄糖攝取增加大約40%[13]。與Akt對GLUT4轉(zhuǎn)位的作用類似, 最近一些證據(jù)表明[14], aPKC ζ/λ在胰島素刺激的骨骼肌GLUT4轉(zhuǎn)位和葡萄糖攝取中也起著重要作用, aPKC ζ/λ的磷酸化激活可以促進胰島素刺激的GLUT4的轉(zhuǎn)位和L6肌管對葡萄糖的攝取 。PIP3與aPKC ζ/λ的調(diào)節(jié)域結(jié)合導(dǎo)致aPKC ζ/λ的激活, 進而促進GLUT4的轉(zhuǎn)位[15]。

雖然通過Akt刺激骨骼肌內(nèi)GLUT4轉(zhuǎn)位的精確分子機制仍然不是很清晰, 但相對分子量為160 000 的Akt底物AS160被認為是Akt介導(dǎo)GLUT4轉(zhuǎn)位的一個重要的調(diào)控分子[16]。AS160是一種可以與Rab蛋白發(fā)生特異性作用的GTP 酶激活蛋白。Rab蛋白是細胞內(nèi)囊泡運輸?shù)姆肿娱_關(guān), 其通過與上游調(diào)控因子以及下游效應(yīng)子的相互作用, 參與了囊泡的形成、轉(zhuǎn)運、粘附、錨定和融合等過程。AS160被認為通過與Rab蛋白相互作用參與了Akt對GLUT4的轉(zhuǎn)位調(diào)節(jié)[17-20]。當(dāng)AS160的Ser588和Thr642位點突變?yōu)楸彼釙r,可以顯著抑制胰島素刺激的GLUT4轉(zhuǎn)位[17], 顯示AS160在胰島素刺激的GLUT4的轉(zhuǎn)位中發(fā)揮著重要作用。但也有研究表明[21], Akt促進GLUT4轉(zhuǎn)位過程的調(diào)節(jié)是非AS160依賴的, 并且已證明其他參與GLUT4轉(zhuǎn)位的Akt底物, 如含F(xiàn)YVE指磷酸肌醇激酶(FYVE finger-containing phosphoinositide kinase, PIKfyve)[22]。Roach等[23]研究表明, 與AS160關(guān)系密切的TBC1域家族成員1(TBC1 domain family member 1, TBCID1)也有類似的可以被Akt磷酸化的位點。可見Akt促進GLUT4轉(zhuǎn)位過程中AS160的作用仍然撲朔迷離, 很有可能AS160和其他Akt底物一起共同參與了GLUT4的轉(zhuǎn)位過程。

1.3 AMPK信號通路與骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達

除PI3K/Akt信號通路，AMPK的激活也可以促進GLUT4的轉(zhuǎn)位和表達。5-氨基咪唑-4-甲酰胺核苷酸(5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, AICAR)(AMPK激活劑)激活A(yù)MPK后可以上調(diào)大鼠比目魚肌細胞以及原代培養(yǎng)的肌細胞的葡萄糖攝取和GLUT4 mRNA的表達, 提示GLUT4是AMPK 參與糖代謝調(diào)節(jié)的重要下游靶點[24,25]。Hommes等[26]研究表明，給大鼠注射AICAR引起AMPK的激活，引起大鼠腓腸肌內(nèi)GLUT4的蛋白表達增加。李蕾等[27]研究表明, AMPK可以通過調(diào)節(jié)糖代謝的下游靶蛋白, 增加GLUT4的轉(zhuǎn)位, 進而增強肌肉胰島素敏感性。有研究報道[1], 在AMPK活化的過程中同樣會激活A(yù)S160。因此，AS160可能是調(diào)節(jié)骨骼肌內(nèi)GLUT4轉(zhuǎn)位的PI3K/Akt和AMPK信號通路的一個關(guān)鍵交匯點。但胰島素刺激和AMPK激活對AS160的影響似乎是通過兩個不同的通路。渥曼青霉素(PI3K抑制劑)可以抑制胰島素對離體大鼠骨骼肌AS160的磷酸化效果，但AICAR所致AMPK激活和AS160磷酸化增加并不涉及Akt的磷酸化改變[28]。

2 PI3K/Akt和AMPK信號通路在運動影響嚙齒動物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達中的作用

2.1 PI3K/Akt和AMPK信號通路存在復(fù)雜的交互作用

PI3K/Akt和AMPK信號通路并不是彼此孤立，而是存在復(fù)雜的交互作用。首先，AMPK對PI3K/ Akt信號通路可以發(fā)揮雙向調(diào)節(jié)作用。有研究者認為[28-31]，AMPK的激活以及AICAR的使用可以促進IRS、PI3K和Akt等多種PI3K/Akt信號通路分子的活性增加。通過AICAR激活小鼠C2C12肌管的AMPK, 結(jié)果表明AMPK的激活與IRS-1的Ser789位點的磷酸化之間存在直接的相互作用[30]。Jakobsen等[32]研究表明，AMPK的激活可以引起小鼠C2C12肌管的IRS-1的Ser789位點的磷酸化水平增加，進而引起PI3K的活性增加。但Tzatsos等[33]報道，AMPK的激活可以促進IRS-1的Ser794位點磷酸化，進而抑制PI3K/Akt信號通路。而IRS-1的Ser794位點磷酸化增加對PI3K/Akt信號通路的抑制可以導(dǎo)致GLUT4的轉(zhuǎn)位減少[34-36]。其次, PI3K/Akt信號通路可以調(diào)節(jié)AMPK的活性，比如Akt的激活可以下調(diào)AMPK的活性[37,38]。Rider等[39]認為，Akt所致的AMPK的Ser487或Ser491位點的磷酸化是胰島素引起AMPK活性下降的關(guān)鍵步驟。

Liu等[40]研究表明，高脂喂養(yǎng)引起大鼠骨骼肌內(nèi)AMPKα的表達和活性受損，而二甲雙胍激活A(yù)MPK后可以明顯改善高脂飲食誘導(dǎo)的胰島素抵抗，提示AMPK的活化與胰島素信號通路之間存在關(guān)聯(lián)，而AMPK活性的下降可能會加速胰島素抵抗和代謝異常的進展。Jessen等[41]報道，運動激活A(yù)MPK后，可以通過刺激GLUT4的表達調(diào)節(jié)Wistar大鼠骨骼肌的胰島素敏感性。那么在運動影響骨骼肌GLUT4的轉(zhuǎn)位和表達中PI3K/Akt和AMPK信號通路是否共同發(fā)揮了作用呢？

2.2 PI3K/Akt信號通路在運動影響骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達中的作用

對骨骼肌胰島素抵抗的研究中, PI3K/Akt信號通路受到眾多研究者的關(guān)注，但Krook等[42]認為運動對骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達的影響與PI3K/Akt信號通路無關(guān)。對肥胖Zucker大鼠的研究表明，運動可以上調(diào)GLUT4的蛋白表達，但IRS-1的酪氨酸磷酸化水平并無明顯變化[43]。這些研究似乎暗示PI3K/Akt信號通路在運動調(diào)節(jié)骨骼肌內(nèi)GLUT4的轉(zhuǎn)位和表達中并不起作用。然而，有研究者持不同意見，Chibalin等[44]的研究表明，游泳運動可增強Wistar大鼠IRS-2、PI3K和Akt的活性，同時增加GLUT4的蛋白表達。研究結(jié)果的不一致可能與采用的動物模型、使用的干預(yù)手段及檢測的信號分子等不同有關(guān)。

2.3 AMPK信號通路在運動影響骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達中的作用

AMPK信號通路在運動增加GLUT4轉(zhuǎn)位和表達中發(fā)揮重要作用。一方面, 運動可以誘導(dǎo)GLUT4的轉(zhuǎn)位，其機制涉及AMPK信號通路[45]。另一方面，運動可以通過激活A(yù)MPK信號通路增加骨骼肌GLUT4 mRNA和蛋白表達[46]。有研究者認為[42], AMPK是通過非胰島素依賴的機制增加骨骼肌葡萄糖攝取, 并有一些研究者對此機制進行了深入探討。有研究者報道[47], AMPK可以通過直接磷酸化過氧化物酶體增殖活化受體γ輔助活化因子1α(α subunit of peroxisome proliferators-activated receptor-γ coactivator-1, PGC-1α)調(diào)節(jié)骨骼肌GLUT4的表達。還有研究者認為[48,49], AMPK可以通過對p38分裂原激活的蛋白激酶(p38 mitogen activated protein kinases, p38MAPK)或內(nèi)皮型一氧化氮合酶(endothelial nitric oxide synthase，eNOS)的作用刺激GLUT4轉(zhuǎn)位。此外，AMPK的主要上游激酶(liver kinase B1, LKB1)可能也參與了骨骼肌葡萄糖攝取。據(jù)報道[50], 骨骼肌缺乏LKB1導(dǎo)致肌肉收縮誘導(dǎo)的葡萄糖攝取受到抑制。值得關(guān)注的是, 抑制AMPK活性對肌肉收縮誘導(dǎo)的小鼠骨骼肌葡萄糖攝取并無明顯影響[51,52]?？紤]到這些研究結(jié)果存在的差異，有必要進一步審查AMPK信號通路在運動影響骨骼肌內(nèi)GLUT4轉(zhuǎn)運和表達中的作用。

2.4 PI3K/Akt和AMPK信號通路可能共調(diào)運動對骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達的影響

早期的研究表明, 胰島素和運動通過不同的信號傳導(dǎo)機制促進GLUT4轉(zhuǎn)位和葡萄糖攝取。然而對PI3K下游的胰島素信號分子的進一步研究表明, aPKC ζ/λ在胰島素和運動刺激小鼠肌肉內(nèi)GLUT4轉(zhuǎn)位和葡萄糖攝取中均發(fā)揮了作用[53,54]。Lessard 等[55]研究表明，運動訓(xùn)練可以增加高脂喂養(yǎng)大鼠骨骼肌AMPKα活性，同時可通過增強胰島素信號通路，促進葡萄糖攝取。這些研究提示PI3K/Akt和AMPK信號通路可能共調(diào)運動對骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達的影響。

有研究者報道，在某些情況下Akt的激活與PI3K之間存在不一致[55]，原因可能與Akt存在非PI3K依賴途徑調(diào)節(jié)有關(guān)，如鈣/鈣調(diào)素依賴性蛋白激酶(calcium-calmodulin dependent protein kinase，CaMK)的活化可直接磷酸化Akt的Thr308位點[56]。值得注意的是，CaMK 除了可調(diào)節(jié)Akt的活性外，還可影響AMPK的激活。李良剛等[25]認為，AMPK可能位于CaMK途徑的下游來調(diào)節(jié)骨骼肌細胞GLUT4 mRNA的表達?？梢?，AMPK信號通路與胰島素信號通路在調(diào)節(jié)運動引起的骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達方面存在密切的聯(lián)系，CaMK可能參與了這種聯(lián)系。

很多研究者[57-59]認為AMPKα的Thr172位點磷酸化是其激活的關(guān)鍵步驟。但有研究表明[60], AMPKα的Ser485位點的磷酸化也參與了AMPK活性的調(diào)節(jié)。值得關(guān)注的是，AMPKα的 Ser485位點是一個自我磷酸化位點，并且此位點是Akt的一個靶點，即Akt可以通過磷酸化AMPK的Ser485位點調(diào)節(jié)AMPK的活性。那么，Akt對AMPK的Ser485位點的調(diào)節(jié)作用是否參與了運動對GLUT4的轉(zhuǎn)位和表達的影響呢？這些問題均有待于進一步的研究給予證實。除AMPK信號通路，運動時還存在其它機制參與了對骨骼肌葡萄糖攝取的調(diào)節(jié)。有研究顯示[61]，AMPK失活的轉(zhuǎn)基因小鼠在缺氧或AICAR激活后己糖攝取能力被完全阻斷，但收縮刺激的己糖攝取只是部分地被抑制。因此，運動刺激的骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達增加很可能是多條信號通路共同作用的結(jié)果，而非PI3K依賴的Akt信號通路很可能參與其中。

3 小結(jié)

由于PI3K/Akt和AMPK信號通路之間存在復(fù)雜的交互作用，并且二者均與骨骼肌內(nèi)GLUT4的轉(zhuǎn)位和表達有關(guān)，因此本文對近年來關(guān)于GLUT4的轉(zhuǎn)位和表達的運動激活以及PI3K/ Akt和AMPK信號通路介導(dǎo)運動改善嚙齒動物骨骼肌葡萄糖攝取的研究進展進行了綜述，但是運動能否通過PI3K/Akt或非PI3K依賴性Akt信號通路以及AMPK信號通路共調(diào)運動刺激的GLUT4的轉(zhuǎn)位和表達仍然存在諸多的不確定性，對于可能聯(lián)系這種共調(diào)作用的具體分子機制依然不甚明了。所以進一步明確運動刺激下參與GLUT4轉(zhuǎn)位和表達的多種信號通路的作用，尤其是深究運動調(diào)控的GLUT4改變是否涉及AMPK和PI3K/Akt信號通路之間的交互作用是有必要的，在這方面的研究進展將有助于胰島素抵抗相關(guān)慢性疾病的防治。

[1] Habets DD, Luiken JJ, Ouwens M, et al. Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake[J]. Front Physiol, 2012, 3: 361.

[2] Jessen N, Goodyear LJ. Contraction signaling to glucose transport in skeletal muscle[J]. J Appl Physiol (1985), 2005, 99(1):330-337.

[3] 趙海燕, 王勇, 馬永平, 等. 胰島素信號轉(zhuǎn)導(dǎo)障礙與胰島素抵抗[J]. 新醫(yī)學(xué), 2010, 41(4):267-271.

[4] Ryder JW, Yang J, Galuska D, et al. Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients[J]. Diabetes, 2000, 49(4):647-654.

[5] Zisman A, Peroni OD, Abel ED, et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance[J]. Nat Med, 2000, 6(8): 924-928.

[6] Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4[J]. Nat Rev Mol Cell Biol, 2002, 3(4):267-277.

[7] Huang S, Czech MP. The GLUT4 glucose transporter[J]. Cell Metab, 2007, 5(4):237-252.

[8] Larance M, Ramm G, James DE. The GLUT4 code[J]. Mol Endocrinol , 2008, 22(2):226-233.

[9] Thong FS, Dugani CB, Klip A. Turning signals on and off: GLUT4 traffic in the insulin- signaling highway[J]. Physiology (Bethesda), 2005, 20(4):271-284.

[10] Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, et al. Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kγ-Akt-AS160 in skeletal muscle cells[J]. Diabetes, 2013, 62(5):1519-1526.

[11] Lee SH, Lee HJ, Lee YH, et al. Korean red ginseng (Panax ginseng) improves insulin sensitivity in high fat fed Sprague-Dawley rats[J]. Phytother Res, 2012, 26(1):142-147.

[12] Sasaki T, Sasaki J, Sakai T, et al. The physiology of phosphoinositides[J]. Biol Pharm Bull, 2007, 30(9):1599-1604.

[13] Machado UF, Schaan BD, Seraphim PM. Glucose transporters in the metabolic syndrome[J]. Arq Bras Endocrinol Metabol , 2006, 50(2):177-189.

[14] Bandyopadhyay G, Kanoh Y, Sajan MP, et al. Effects of adenoviral gene transfer of wild-type, constitutively active, and kinase-defective protein kinase C-lambda on insulinstimulated glucose transport in L6 myotubes[J]. Endocrinology, 2000, 141(11):4120-4127.

[15] Farese RV. Function and dysfunction of aPKC isoforms for glucose transport in insulin- sensitive and insulin-resistantstates[J]. Am J Physiol Endocrinol Metab, 2002, 283(1):E1-11.

[16] Eguez L, Lee A, Chavez JA, et al. Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein [J]. Cell Metab, 2005, 2(4):263-272.

[17] Sano H, Kane S, Sano E, et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation[J]. J Biol Chem, 2003, 278(17):14599-14602.

[18] Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action[J]. Nat Rev Mol Cell Biol, 2006, 7(2):85-96.

[19] Frφig C, Richter EA. Improved insulin sensitivity after exercise: focus on insulin signaling[J]. Obesity (Silver Spring), 2009, 17(S3):S15-20.

[20] Chen S, Wasserman DH, MacKintosh C, et al. Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking[J]. Cell Metab, 2011, 13(1):68-79.

[21] Bai L, Wang Y, Fan J, et al. Dissecting multiple steps of GLUT4 trafficking and identifying the sites of insulin action [J]. Cell Metab, 2007, 5(1):47-57.

[22] Berwick DC, Dell GC, Welsh GI, et al. Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles[J]. J Cell Sci, 2004, 117(Pt 25):5985-5993.

[23] Roach WG, Chavez JA, Miinea CP, et al. Substrate specificity and effect on GLUT4 translocation of Rab GTPase-activating protein TBC1D1[J]. Biochem J, 2007, 403(2):353-358.

[24] Sakoda H, Ogihara T, Anai M, et al. Activation of AMPK is essential for AICAR-induced glucose uptake by skeletal muscle but not adipocytes[J]. Am J Physiol Endocrinol Metab, 2002, 282(6):1239-1244.

[25] 李良剛, 陳槐卿. CaMK和AMPK信號通路能共調(diào)收縮信號誘導(dǎo)的骨骼肌細胞GLUT4 基因轉(zhuǎn)錄[J]. 生物化學(xué)與生物物理進展, 2009, 36(4):471-479.

[26] Holmes BF, Kurth-Kraczek EJ, Winder WW. Chronic activation of 5’-AMP-activated protein kinase increases GLUT4, hexokinase, and glycogen in muscle[J]. J Appl Physiol (1985), 1999, 87(5):1990-1995.

[27] 李蕾, 李之俊. 運動改善胰島素抵抗與腺苷酸活化蛋白激酶關(guān)系的研究進展[J]. 生理學(xué)報, 2014, 66(2):231-240.

[28] Bruss MD, Arias EB, Lienhard GE, et al. Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity[J]. Diabetes, 2005, 54(1):41-50.

[29] Tao R, Gong J, Luo X, et al. AMPK exerts dual regulatory effects on the PI3K pathway [J]. J Mol Signal, 2010, 5(1):1.

[30] Jakobsen SN, Hardie DG, Morrice N, et al. 5’-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamideriboside[J]. J Biol Chem, 2001, 276(50):46912-46916.

[31] 黃德強, 羅凌玉, 王麗麗, 等. AMPK在胰島素信號轉(zhuǎn)導(dǎo)通路中的作用[J]. 中國細胞生物學(xué)學(xué)報, 2011, 33(11):1220-1229.

[32] Jakobsen SN, Hardie DG, Morrice N, et al. 5’ AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside[J]. J Biol Chem, 2001, 276(50):46912-46916.

[33] Tzatsos A, Tsichlis PN. Energy depletion inhibits phosphatidylinositol 3-kinase/Akt signaling and induces apoptosis via AMP-activated protein kinase-dependent phosphorylation of IRS-1 at Ser-794[J]. J Biol Chem , 2007, 282(25):18069-18082.

[34] Ni YG, Wang N, Cao DJ, et al. FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases[J]. Proc Natl Acad Sci U S A, 2007, 104(51):20517-20522.

[35] Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4[J]. Nat Rev Mol Cell Biol, 2012, 13 (6):383-396.

[36] Watson RT, Pessin JE. Bridging the GAP between insulin signaling and GLUT4 translocation[J]. Trends Biochem Sci , 2006, 31(4):215-222.

[37] Hahn-Windgassen A, Nogueira V, Chen CC, et al. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity[J]. J Biol Chem, 2005, 280(37):32081-32089.

[38] Kovacic S, Soltys CL, Barr AJ, et al. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart[J]. J Biol Chem, 2003, 278(41):39422-39427.

[39] Rider MH. The ubiquitin-associated domain of AMPK-related protein kinases allows LKB1-induced phosphorylation and activation[J]. Biochem J, 2006, 394(Pt3):e7-9.

[40] Liu Y, Wan Q, Guan Q, et al. High-fat diet feeding impairs both the expression and activity of AMPKα in rat’ skeletal muscle [J]. Biochem Biophys Res Commun, 2006, 339(2):701-707. [41] Jessen N, Pold R, Buhl ES, et al. Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles[J]. J Appl Physiol(1985), 2003, 94 (4):1373-1379.

[42] Krook A, Wallberg-Henriksson H, Zierath JR. Sending the signal: molecular mechanisms regulating glucose uptake[J]. Med Sci Sports Exerc, 2004, 36(7):1212-1217.

[43] Christ CY, Hunt D, Hancock J, et al. Exercise training improves muscle insulin resistance but not insulin receptor signaling in obese Zucker rats[J]. J Appl Physiol (1985), 2002, 92(2):736-744.

[44] Chibalin AV, Yu M, Ryder JW, et al. Exercise-induced changes in expression and activity of proteins involved in insulin signaltransduction in skeletal muscle: differential effects on insulinreceptor substrates 1 and 2[J]. Pros Natl Acad Sei U S A, 2000, 97(1):38-43.

[45] Olmes B, Dohm GL. Regulation of GLUT4 gene expression during exercise[J]. Med Sci Sports Exerc, 2004, 36(7):1202-1206.

[46] Holmes B, Dohm GL. Regulation of GLUT4 gene expression during exercise[J]. Med Sci Sports Exerc, 2004, 36(7):1202-1206.

[47] J ger S, Handschin C, St-Pierre J, et al. AMP-activaed protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α[J]. Proc Natl Acad Sci U S A, 2007, 104(29):12017-12022.

[48] Li J, Hu X, Selvakumar P, et al. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle[J]. Am J Physiol Endocrinol Metab, 2004, 287(5):E834-841.

[49] Li J, Miller EJ, Ninomiya-Tsuji J, et al. AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart[J]. Circ Res, 2005, 97(9):872-879.

[50] Sakamoto K, McCarthy A, Smith D, et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction[J]. EMBO J, 2005, 24(10):1810-1820.

[51] Atherton PJ, Babraj J, Smith K, et al. Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation[J]. FASEB J, 2005, 19(7):786-788.

[52] J rgensen SB, Viollet B, Andreelli F, et al. Knockout of the alpha2 but not alpha1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle[J]. J Biol Chem, 2004, 279(2):1070-1079.

[53] Farese RV, Sajan MP, Yang H, et al. Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes[J]. J Clin Invest, 2007, 117(8): 2289-2301.

[54] Richter EA, Vistisen B, Maarbjerg SJ, et al. Differential effect of bicycling exercise intensity on activity and phosphorylation of atypical protein kinase C and extracellular signalregulated protein kinase in skeletal muscle[J]. J Physiol, 2004, 560(Pt 3):909-918.

[55] Lessard SJ, Rivas DA, Chen ZP, et al. Tissue-specific effects of rosiglitazone and exercise in the treatment of lipid-induced insulin resistance[J]. Diabetes, 2007, 56(7):1856-1864. [56] Kumari S, Liu X, Nguyen T, et al. Distinct phosphorylation patterns underlie Akt activation by different survival factors in neurons[J]. Brain Res Mol Brain Res, 2001, 96(1-2):157-162.

[57] Leclerc I, Rutter GA. AMP-activated protein kinase: a new beta-cell glucose sensor: Regulation by amino acids and calcium ions[J]. Diabetes, 2004, 53(S3):S67-74.

[58] Zang M, Zuccollo A, Hou X, et al. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells[J]. J Biol Chem, 2004, 279(46):47898-47905.

[59] Hardie DG. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status[J]. Endocrinology, 2003, 144(12):5179-5183.

[60] Horman S, Vertommen D, Heath R, et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491[J]. J Biol Chem , 2006, 281 (9):5335-5340.

[61] Mu J, Brozinick JT Jr, Valladares O, et al. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle[J]. Mol Cell, 2001, 7(5):1085-1094.

PI3K/Akt and AMPK Signaling Pathway and Effect of Exercise on Rodent Skeletal Muscle GLUT4 Translocation and Expression

ZHANG Yun-li, WANG Lin, LIU Tie-min
(Liaocheng University, Liaocheng 252059, China)

Skeletal muscles play an important role in glucose homeostasis. The translocation and expression changes of glucose transporter 4 (GLUT4) as one of the most important glucose transporter proteins in skeletal muscle are closely associated with insulin resistance. This paper reviewed the recent research progress on the exercise-induced translocation and expression of GLUT4 as well as the improvement of exercise-induced glucose uptake by phosphatidylinositol 3-kinases (PI3K) / protein kinase B (Akt) and AMP-activated protein kinase (AMPK) signaling pathways in rodent skeletal muscle. The purpose of this paper is to clearly understand the mechanism underlying GLUT4 translocation and expression in rodent skeletal muscles.

Skeletal muscle; Exercise; Insulin resistance; Glucose transporter 4 (GLUT4); Phosphatidylinositol 3-kinases (PI3K); Protein kinase B (Akt); AMP-activated protein kinase (AMPK)

Q95-33

A

1674-5817(2017)01-0076-07

10.3969/j.issn.1674-5817.2017.01.017

2016-06-15

山東省自然科學(xué)基金資助項目(ZR2011CM040)

張云麗(1977-), 女, 講師,

E-mail: zhangyunli@lcu.edu.cn