Rac1在运动促进骨骼肌葡萄糖摄取过程中的作用研究进展
摘要
营养过剩和缺乏运动将引起肥胖、2型糖尿病(T2DM)等代谢性疾病的发生,胰岛素抵抗(in-sulin resistance,IR)是众多代谢性疾病的重要病理生理学基础。目前普遍认为运动通过调节机体糖代谢可明显改善IR的症状,已被广泛应用于肥胖、T2DM、高脂血症等一系列代谢性疾病的防治,但目前对运动防治代谢性疾病的确切调节机制仍不完全清楚。最新研究发现,哺乳动物组织细胞内重要信号转导因子Ras-相关C3肉毒杆菌毒素底物1(Ras-related C3 botulinum toxin substrate 1,Rac1)参与肌动蛋白细胞骨架重构,调节骨骼肌细胞葡萄糖转运体4(Glucose transporter 4,GLUT4)转位,在运动促进骨骼肌葡萄糖转运过程中发挥重要作用。本文对Rac1在运动促进骨骼肌组织葡萄糖摄取中的作用研究进展进行综述,以期为揭示运动防治代谢性疾病的机制提供理论依据。
引文
[1]Marinkovic G,Heemskerk N,van Buul JD,et al.The insand outs of small GTPase Rac1 in the vasculature[J].JPharmacol Exp Ther,2015,354(2):91-102.
[2]Hodge RG,Ridley AJ.Regulating Rho GTPases andtheir regulators[J].Nat Rev Mol Cell Biol,2016,17(8):496-510.
[3]Cuadrado A,Martin-Moldes Z,Ye J,et al.Transcription factors NRF2 and NF-kappa B are coordinated effectorsof the Rho family,GTP-binding protein RAC1 during in-flammation[J].The J Biol Chem,2014,289(22):15244-15258.
[4]Aksamitiene E,Kiyatkin A,Kholodenko BN.Cross-talkbetween mitogenic Ras/MAPK and survival PI3K/Aktpathways:a fine balance[J].Biochem Soc Trans,2012,40(1):139-146.
[5]Charrasse S,Comunale F,Fortier M,et al.M-cadherin ac-tivates Rac1 GTPase through the Rho-GEF trio duringmyoblast fusion[J].Mol Biol Cell,2007,18(5):1734-1743.
[6]Bentzinger CF,von Maltzahn J,Dumont NA,et al.Wnt7astimulates myogenic stem cell motility and engraftment re-sulting in improved muscle strength[J].J Cell Biol,2014,205(1):97-111.
[7]Jensen TE,Sylow L,Rose AJ,et al.Contraction-stimulat-ed glucose transport in muscle is controlled by AMPKand mechanical stress but not sarcoplasmatic reticulumCa(2+)release[J].Mol Metab,2014,3(7):742-753.
[8]Ferri N,Contini A,Bernini SK,et al.Role of small GT-Pase protein Rac1 in cardiovascular diseases:develop-ment of new selective pharmacological inhibitors[J].J Car-diovasc Pharmacol,2013,62(5):425-435.
[9]Bid HK,Roberts RD,Manchanda PK,et al.RAC1:anemerging therapeutic option for targeting cancer angiogen-esis and metastasis[J].Mol Cancer Ther,2013,12(10):1925-1934.
[10]Veluthakal R,Tunduguru R,Arora DK,et al.VAV2,aguanine nucleotide exchange factor for Rac1,regulatesglucose-stimulated insulin secretion in pancreatic betacells[J].Diabetologia,2015,58(11):2573-2581.
[11]Sylow L,Nielsen IL,Kleinert M,et al.Rac1 governs exer-cise-stimulated glucose uptake in skeletal musclethrough regulation of GLUT4 translocation in mice[J].JPhysiol,2016,594(17):4997-5008.
[12]Klip A,Sun Y,Chiu TT,et al.Signal transduction meetsvesicle traffic:the software and hardware of GLUT4 trans-location[J].Am J Physiol Cell Physiol,2014,306(10):C879-C886.
[13]Huang S,Czech MP.The GLUT4 glucose transporter[J].Cell Metab,2007,5(4):237-252.
[14]Sylow L,Jensen TE,Kleinert M,et al.Rac1 signaling isrequired for insulin-stimulated glucose uptake and isdysregulated in Insulin-Resistant murine and human skel-etal muscle[J].Diabetes,2013,62(6):1865-1875.
[15]Sylow L,Jensen TE,Kleinert M,et al.Rac1 is a novelregulator of contraction-stimulated glucose uptake inskeletal muscle[J].Diabetes,2013,62(4):1139-1151.
[16]Je Bailey L,Wanono O,Niu W,et al.Ceramide-and oxi-dant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in musclecells[J].Diabetes,2007,56(2):394-403.
[17]Je Bailey L,Rudich A,Huang X,et al.Skeletal musclecells and adipocytes differ in their reliance on TC10and Rac for insulin-induced actin remodeling[J].Mol En-docrinol,2004,18(2):359-372.
[18]Khayat ZA,Tong P,Yaworsky K,et al.Insulin-inducedactin filament remodeling colocalizes actin with phosphati-dylinositol 3-kinase and GLUT4 in L6 myotubes[J].JCell Sci,2000,113 Pt 2:279-290.
[19]Ueda S,Kataoka T,Satoh T.Activation of the small GT-Pase Rac1 by a specific guanine-nucleotide-exchangefactor suffices to induce glucose uptake into skeletal-muscle cells[J].Biol Cell,2008,100(11):645-657.
[20]Chiu TT,Sun Y,Koshkina A,et al.Rac-1 superactiva-tion triggers insulin-independent glucose transporter 4(GLUT4)translocation that bypasses signaling defects ex-erted by c-Jun N-terminal kinase(JNK)-and ceramide-induced insulin resistance[J].J Biol Chem,2013,288(24):17520-17531.
[21]Ueda S,Kitazawa S,Ishida K,et al.Crucial role of thesmall GTPase Rac1 in insulin-stimulated translocation ofglucose transporter 4 to the mouse skeletal muscle sarco-lemma[J].FASEB J,2010,24(7):2254-2261.
[22]Sylow L,Kleinert M,Richter EA,et al.Exercise-stimulat-ed glucose uptake-regulation and implications for glycae-mic control[J].Nat Rev Endocrinol,2017,13(3):133-148.
[23]Sylow L,M?ller LL,Kleinert M,et al.Rac1--a novel reg-ulator of contraction-stimulated glucose uptake in skele-tal muscle[J].Exp Physiol,2014,99(12):1574-1580.
[24]Hu F,Li N,Li Z,et al.Electrical pulse stimulation induc-es GLUT4 translocation in a Rac-Akt-dependent man-ner in C2C12 myotubes[J].FEBS Lett,2018,592(4):644-654.
[25]Manser E,Leung T,Salihuddin H,et al.A brain serine/threonine protein kinase activated by Cdc42 and Rac1[J].Nature,1994,367(6458):40-46.
[26]Zhou Y,Jiang D,Thomason DB,et al.Laminin-inducedactivation of Rac1 and JNKp46 is initiated by Src fami-ly kinases and mimics the effects of skeletal muscle con-traction[J].Biochemistry,2007,46(51):14907-14916.
[27]Lee YM,Lee JO,Jung JH,et al.Retinoic acid leads tocytoskeletal rearrangement through AMPK-Rac1 and stim-ulates glucose uptake through AMPK-p38 MAPK inskeletal muscle cells[J].J Biol Chem,2008,283(49):33969-33974.
[28]You GY,Lee JO,Kim JH,et al.Tiam-1,a GEF forRac1,plays a critical role in metformin-mediated glucoseuptake in C2C12 cells[J].Cell Signal,2013,25(12):2558-2565.
[29]Sylow L,Moller LLV,Kleinert M,et al.Rac1 and AMPKaccount for the majority of muscle glucose uptake stimu-lated by ex vivo contraction but not in vivo Exercise[J].Diabetes,2017,66(6):1548-1559.
[2]Hodge RG,Ridley AJ.Regulating Rho GTPases andtheir regulators[J].Nat Rev Mol Cell Biol,2016,17(8):496-510.
[3]Cuadrado A,Martin-Moldes Z,Ye J,et al.Transcription factors NRF2 and NF-kappa B are coordinated effectorsof the Rho family,GTP-binding protein RAC1 during in-flammation[J].The J Biol Chem,2014,289(22):15244-15258.
[4]Aksamitiene E,Kiyatkin A,Kholodenko BN.Cross-talkbetween mitogenic Ras/MAPK and survival PI3K/Aktpathways:a fine balance[J].Biochem Soc Trans,2012,40(1):139-146.
[5]Charrasse S,Comunale F,Fortier M,et al.M-cadherin ac-tivates Rac1 GTPase through the Rho-GEF trio duringmyoblast fusion[J].Mol Biol Cell,2007,18(5):1734-1743.
[6]Bentzinger CF,von Maltzahn J,Dumont NA,et al.Wnt7astimulates myogenic stem cell motility and engraftment re-sulting in improved muscle strength[J].J Cell Biol,2014,205(1):97-111.
[7]Jensen TE,Sylow L,Rose AJ,et al.Contraction-stimulat-ed glucose transport in muscle is controlled by AMPKand mechanical stress but not sarcoplasmatic reticulumCa(2+)release[J].Mol Metab,2014,3(7):742-753.
[8]Ferri N,Contini A,Bernini SK,et al.Role of small GT-Pase protein Rac1 in cardiovascular diseases:develop-ment of new selective pharmacological inhibitors[J].J Car-diovasc Pharmacol,2013,62(5):425-435.
[9]Bid HK,Roberts RD,Manchanda PK,et al.RAC1:anemerging therapeutic option for targeting cancer angiogen-esis and metastasis[J].Mol Cancer Ther,2013,12(10):1925-1934.
[10]Veluthakal R,Tunduguru R,Arora DK,et al.VAV2,aguanine nucleotide exchange factor for Rac1,regulatesglucose-stimulated insulin secretion in pancreatic betacells[J].Diabetologia,2015,58(11):2573-2581.
[11]Sylow L,Nielsen IL,Kleinert M,et al.Rac1 governs exer-cise-stimulated glucose uptake in skeletal musclethrough regulation of GLUT4 translocation in mice[J].JPhysiol,2016,594(17):4997-5008.
[12]Klip A,Sun Y,Chiu TT,et al.Signal transduction meetsvesicle traffic:the software and hardware of GLUT4 trans-location[J].Am J Physiol Cell Physiol,2014,306(10):C879-C886.
[13]Huang S,Czech MP.The GLUT4 glucose transporter[J].Cell Metab,2007,5(4):237-252.
[14]Sylow L,Jensen TE,Kleinert M,et al.Rac1 signaling isrequired for insulin-stimulated glucose uptake and isdysregulated in Insulin-Resistant murine and human skel-etal muscle[J].Diabetes,2013,62(6):1865-1875.
[15]Sylow L,Jensen TE,Kleinert M,et al.Rac1 is a novelregulator of contraction-stimulated glucose uptake inskeletal muscle[J].Diabetes,2013,62(4):1139-1151.
[16]Je Bailey L,Wanono O,Niu W,et al.Ceramide-and oxi-dant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in musclecells[J].Diabetes,2007,56(2):394-403.
[17]Je Bailey L,Rudich A,Huang X,et al.Skeletal musclecells and adipocytes differ in their reliance on TC10and Rac for insulin-induced actin remodeling[J].Mol En-docrinol,2004,18(2):359-372.
[18]Khayat ZA,Tong P,Yaworsky K,et al.Insulin-inducedactin filament remodeling colocalizes actin with phosphati-dylinositol 3-kinase and GLUT4 in L6 myotubes[J].JCell Sci,2000,113 Pt 2:279-290.
[19]Ueda S,Kataoka T,Satoh T.Activation of the small GT-Pase Rac1 by a specific guanine-nucleotide-exchangefactor suffices to induce glucose uptake into skeletal-muscle cells[J].Biol Cell,2008,100(11):645-657.
[20]Chiu TT,Sun Y,Koshkina A,et al.Rac-1 superactiva-tion triggers insulin-independent glucose transporter 4(GLUT4)translocation that bypasses signaling defects ex-erted by c-Jun N-terminal kinase(JNK)-and ceramide-induced insulin resistance[J].J Biol Chem,2013,288(24):17520-17531.
[21]Ueda S,Kitazawa S,Ishida K,et al.Crucial role of thesmall GTPase Rac1 in insulin-stimulated translocation ofglucose transporter 4 to the mouse skeletal muscle sarco-lemma[J].FASEB J,2010,24(7):2254-2261.
[22]Sylow L,Kleinert M,Richter EA,et al.Exercise-stimulat-ed glucose uptake-regulation and implications for glycae-mic control[J].Nat Rev Endocrinol,2017,13(3):133-148.
[23]Sylow L,M?ller LL,Kleinert M,et al.Rac1--a novel reg-ulator of contraction-stimulated glucose uptake in skele-tal muscle[J].Exp Physiol,2014,99(12):1574-1580.
[24]Hu F,Li N,Li Z,et al.Electrical pulse stimulation induc-es GLUT4 translocation in a Rac-Akt-dependent man-ner in C2C12 myotubes[J].FEBS Lett,2018,592(4):644-654.
[25]Manser E,Leung T,Salihuddin H,et al.A brain serine/threonine protein kinase activated by Cdc42 and Rac1[J].Nature,1994,367(6458):40-46.
[26]Zhou Y,Jiang D,Thomason DB,et al.Laminin-inducedactivation of Rac1 and JNKp46 is initiated by Src fami-ly kinases and mimics the effects of skeletal muscle con-traction[J].Biochemistry,2007,46(51):14907-14916.
[27]Lee YM,Lee JO,Jung JH,et al.Retinoic acid leads tocytoskeletal rearrangement through AMPK-Rac1 and stim-ulates glucose uptake through AMPK-p38 MAPK inskeletal muscle cells[J].J Biol Chem,2008,283(49):33969-33974.
[28]You GY,Lee JO,Kim JH,et al.Tiam-1,a GEF forRac1,plays a critical role in metformin-mediated glucoseuptake in C2C12 cells[J].Cell Signal,2013,25(12):2558-2565.
[29]Sylow L,Moller LLV,Kleinert M,et al.Rac1 and AMPKaccount for the majority of muscle glucose uptake stimu-lated by ex vivo contraction but not in vivo Exercise[J].Diabetes,2017,66(6):1548-1559.