European Journal of Applied Physiology

, Volume 113, Issue 10, pp 2473–2486 | Cite as

Swimming exercise training-induced left ventricular hypertrophy involves microRNAs and synergistic regulation of the PI3K/AKT/mTOR signaling pathway

  • Zhichao Ma
  • Jie Qi
  • Shuai Meng
  • Baoju Wen
  • Jun Zhang
Original Article



Swimming exercise leads to a nonpathological, physiological left ventricular hypertrophy. However, the potential molecular mechanisms are unknown. We investigated the role of microRNAs (miRNA) regulating the cardiac signal cascades were studied in exercised rats.


Female Wistar rats were assigned into two groups: (1) sedentary control (SC), (2) swimming exercise (SE). The rats in the SE group completed a 1-h swimming exercise, 5 times/week/8-week with 5 % body overload. miRNA, phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3α), phosphatase and tensin homolog (PTEN) and tuberous sclerosis complex 2 (TSC2) gene expression analysis were performed by real-time PCR in heart muscle. Moreover, we assessed cardiac protein expression of ERK1/2, PI3K/AKT/mTOR, PTEN and TSC2.


Cardiac phosphoser473-AKT and phosphoSer2448-mTOR were, respectively, increased by 46 and 38 % in the SE group when compared with SC group. miRNAs-21, 144, and 145 were, respectively, up-regulated in the SE group (152 %, 128, and 101 % relative increases), but miRNA-124 was decreased by 38 %. In SE group, PIK3α (targeted by miRNA-124) gene expression increased by 213 %, and Pten (targeted by miRNAs-21 and 144), and TSC2 (targeted by miRNA-145) were, respectively, decreased by 51 and 55 %. In addition, the swimming exercise increased protein levels of PIK3α (36 %) and phosphoThr1462-TSC2 (48 %), while it decreased PTEN (37 %) and TSC2 (22 %), which induced activation of PI3K/AKT/mTOR signaling pathway.


These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, changing the expression of specific miRNAs targeting the PIK3/AKT/mTOR signaling pathway and its negative regulators.


Swimming Heart Hypertrophy microRNA PI3K ERK 



Atrial natriuretic polypeptide


Left ventricular hypertrophy


Mammalian target of rapamycin




Phosphoinositide-3-kinase catalytic alpha polypeptide






Phosphatase and tensin homolog


Protein kinase C


Tuberous sclerosis complex 2


Skeletal muscle α-actin


α-Myosin heavy chain


β-Myosin heavy chain


  1. Andjelkovic M, Maira SM, Cron P, Parker PJ, Hemmings BA (1999) Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase. Mol Cell Biol 19:5061–5072PubMedGoogle Scholar
  2. Aoyagi T, Matsui T (2011) Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure. Curr Pharm Des 17:1818–1824. doi:10.2174/138161211796390976 PubMedCrossRefGoogle Scholar
  3. Boström P, Mann N, Wu J, Quintero PA, Plovie ER, Panáková D, Gupta RK, Xiao C, MacRae CA, Rosenzweig A, Spiegelman BM (2010) C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 23(143):1072–1083. doi:10.1016/j.cell.2010.11.036 CrossRefGoogle Scholar
  4. Brodbeck D, Cron P, Hemmings BA (1999) A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem 274:9133–9136. doi:10.1074/jbc.274.14.9133 PubMedCrossRefGoogle Scholar
  5. Bueno OF, Molkentin JD (2002) Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 91:776–781. doi:10.1161/01.RES.0000038488.38975.1A PubMedCrossRefGoogle Scholar
  6. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657. doi:10.1126/science.296.5573.1655 PubMedCrossRefGoogle Scholar
  7. Cao P, Zhou L, Zhang J, Zheng F, Wang H, Ma D, Tian J (2013) Comprehensive expression profiling of microRNAs in laryngeal squamous cell carcinoma. Head Neck 35:720–728. doi:10.1002/hed.23011 PubMedCrossRefGoogle Scholar
  8. Catto JW, Alcaraz A, Bjartell AS, De White Vere R, Evans CP, Fussel S, Hamdy FC, Kallioniemi O, Mengual L, Schlomm T, Visakorpi T (2011) MicroRNA in prostate, bladder, and kidney cancer: a systematic review. Eur Urol 59:671–681. doi:10.1016/j.eururo.2011.01.044 PubMedCrossRefGoogle Scholar
  9. Cheng Y, Ji R, Yue J, Yang J, Liu X, Chen H, Dean DB, Zhang C (2007) MicroRNAs are aberrantly expressed in hypertrophic heart: do they play a role in cardiac hypertrophy? Am J Pathol 170:1831–1840. doi:10.2353/ajpath.2007.061170 PubMedCrossRefGoogle Scholar
  10. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ (2001a) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728–1731. doi:10.1126/science.292.5522.1728 PubMedCrossRefGoogle Scholar
  11. Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ (2001b) Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276:38349–38352. doi:10.1074/jbc.C100462200 PubMedCrossRefGoogle Scholar
  12. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 99:12333–12338. doi:10.1073/pnas.172376399 PubMedCrossRefGoogle Scholar
  13. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng HY, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wymann MP, Backx PH, Penninger JM (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110:737–749. doi:10.1016/S0092-8674(02)00969-8 PubMedCrossRefGoogle Scholar
  14. da Silva Jr ND, Fernandes T, Soci UP, Monteiro AW, Phillips MI, de Oliveira EM (2012) Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis. Med Sci Sports Exerc 44: 1453–1462. doi:10.1249/MSS.0b013e31824e8a36
  15. DeBosch B, Treskov I, Lupu TS, Weinheimer C, Kovacs A, Courtois M, Muslin AJ (2006) Akt1 is required for physiological cardiac growth. Circulation 113:2097–2104. doi:10.1161/CIRCULATIONAHA.105.595231 PubMedCrossRefGoogle Scholar
  16. Dorn GW 2nd (2007) The fuzzy logic of physiological cardiac hypertrophy. Hypertension 49:962–970. doi:10.1161/HYPERTENSIONAHA.106.079426 PubMedCrossRefGoogle Scholar
  17. Etzion S, Etzion Y, DeBosch B, Crawford PA, Muslin AJ (2010) Akt2 deficiency promotes cardiac induction of Rab4a and myocardial beta-adrenergic hypersensitivity. J Mol Cell Cardiol 49:931–940. doi:10.1016/j.yjmcc.2010.08.011 PubMedCrossRefGoogle Scholar
  18. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294:1942–1945. doi:10.1126/science.1066015 PubMedCrossRefGoogle Scholar
  19. Fernandes T, Hashimoto NY, Magalhães FC, Fernandes FB, Casarini DE, Carmona AK, Krieger JE, Phillips MI, Oliveira EM (2011) Aerobic exercise training-induced left ventricular hypertrophy involves regulatory microRNAs, decreased angiotensin-converting enzyme-angiotensin II, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1–7). Hypertension 58:182–189. doi:10.1161/HYPERTENSIONAHA.110.168252 PubMedCrossRefGoogle Scholar
  20. Franchini KG (2012) Focal adhesion kinase—the basis of local hypertrophic signaling domains. J Mol Cell Cardiol 52:485–492. doi:10.1016/j.yjmcc.2011.06.021 PubMedCrossRefGoogle Scholar
  21. Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112:197–208. doi:10.1172/JCI16885 PubMedGoogle Scholar
  22. Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218. doi:10.1016/S0955-0674(99)80028-3 PubMedCrossRefGoogle Scholar
  23. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22. doi:10.1016/j.ccr.2007.05.008 PubMedCrossRefGoogle Scholar
  24. Harfe BD (2005) MicroRNAs in vertebrate development. Curr Opin Genet Dev 15:410–415. doi:10.1016/j.gde.2005.06.012 PubMedCrossRefGoogle Scholar
  25. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol 7:589–600. doi:10.1038/nrm1983 PubMedCrossRefGoogle Scholar
  26. Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412:179–190. doi:10.1042/BJ20080281 PubMedCrossRefGoogle Scholar
  27. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657. doi:10.1038/ncb839 PubMedCrossRefGoogle Scholar
  28. Kaddar T, Rouault JP, Chien WW, Chebel A, Gadoux M, Salles G, Ffrench M, Magaud JP (2009) Two new miR-16 targets: caprin-1 and HMGA1, proteins implicated in cell proliferation. Biol Cell 101:511–524. doi:10.1042/BC20080213 PubMedCrossRefGoogle Scholar
  29. Kim J, Wende AR, Sena S, Theobald HA, Soto J, Sloan C, Wayment BE, Litwin SE, Holzenberger M, LeRoith D, Abel ED (2008) Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol Endocrinol 22:2531–2543. doi:10.1210/me.2008-0265 PubMedCrossRefGoogle Scholar
  30. Kishimoto H, Hamada K, Saunders M, Backman S, Sasaki T, Nakano T, Mak TW, Suzuki A (2003) Physiological functions of Pten in mouse tissues. Cell Struct Funct 28:11–21. doi:10.1247/csf.28.11 PubMedCrossRefGoogle Scholar
  31. Lackey J, Barnett J, Davidson L, Batty IH, Leslie NR, Downes CP (2007) Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling. Oncogene 26:7132–7142. doi:10.1038/sj.onc.1210520 PubMedCrossRefGoogle Scholar
  32. Lang Q, Ling C (2012) MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun 21(426):247–252. doi:10.1016/j.bbrc.2012.08.075 CrossRefGoogle Scholar
  33. Leontieva OV, Paszkiewicz GM, Blagosklonny MV (2012) Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging. Aging-US 4:899–916Google Scholar
  34. Leslie NR, Downes CP (2004) PTEN function: how normal cells control it and tumour cells lose it. Biochem J 382:1–11. doi:10.1042/BJ20040825 PubMedCrossRefGoogle Scholar
  35. Leslie NR, Gray A, Pass I, Orchiston EA, Downes CP (2000) Analysis of the cellular functions of PTEN using catalytic domain and C-terminal mutations: differential effects of C-terminal deletion on signalling pathways downstream of phosphoinositide 3-kinase. Biochem J 346(Pt 3):827–833. doi:10.1042/0264-6021:3460827 PubMedCrossRefGoogle Scholar
  36. Leslie NR, Yang X, Downes CP, Weijer CJ (2007) PtdIns(3,4,5)P(3)-dependent and -independent roles for PTEN in the control of cell migration. Curr Biol 17:115–125. doi:10.1016/j.cub.2006.12.026 PubMedCrossRefGoogle Scholar
  37. Ling HY, Hu B, Hu XB, Zhong J, Feng SD, Qin L, Liu G, Wen GB, Liao DF (2012) MiRNA-21 reverses high glucose and high insulin induced insulin resistance in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue. Exp Clin Endocrinol Diabetes 120:553–559. doi:10.1055/s-0032-1311644 PubMedCrossRefGoogle Scholar
  38. Lynam-Lennon N, Maher SG, Reynolds JV (2009) The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc 84:55–71. doi:10.1111/j.1469-185X.2008.00061.x PubMedCrossRefGoogle Scholar
  39. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378. doi:10.1074/jbc.273.22.13375 PubMedCrossRefGoogle Scholar
  40. Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9:125–128. doi:10.1016/S0962-8924(99)01519-6 PubMedCrossRefGoogle Scholar
  41. Marin TM, Clemente CF, Santos AM, Picardi PK, Pascoal VD, Lopes-Cendes I, Saad MJ, Franchini KG (2008) Shp2 negatively regulates growth in cardiomyocytes by controlling focal adhesion kinase/Src and mTOR pathways. Circ Res 103:813–824. doi:10.1161/CIRCRESAHA.108.179754 PubMedCrossRefGoogle Scholar
  42. Matsui T, Rosenzweig A (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell Cardiol 38:63–71. doi:10.1016/j.yjmcc.2004.11.005 PubMedCrossRefGoogle Scholar
  43. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277:22896–22901. doi:10.1074/jbc.M200347200 PubMedCrossRefGoogle Scholar
  44. McMullen JR, Jennings GL (2007) Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 34:255–262. doi:10.1111/j.1440-1681.2007.04585.x PubMedCrossRefGoogle Scholar
  45. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, Izumo S (2003) Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 100:12355–12360. doi:10.1073/pnas.1934654100 PubMedCrossRefGoogle Scholar
  46. McMullen JR, Sherwood MC, Tarnavski O, Zhang L, Dorfman AL, Shioi T, Izumo S (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050–3055. doi:10.1161/01.CIR.0000130641.08705.45 PubMedCrossRefGoogle Scholar
  47. McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY, Jennings GL (2007) Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 104:612–617. doi:10.1073/pnas.0606663104 PubMedCrossRefGoogle Scholar
  48. Medeiros A, Oliveira EM, Gianolla R, Casarini DE, Negra˜o CE, Brum PC (2004) Swimming training increases cardiac vagal activity and induces cardiac hypertrophy in rats. Braz J Med Biol Res 37:1909–1917. doi:10.1590/S0100-879X2004001200018 PubMedCrossRefGoogle Scholar
  49. Muslin AJ, DeBosch B (2006) Role of Akt in cardiac growth and metabolism. Novartis Found Symp 274:118–126 (discussion 126–131, 152–155, 272–276)Google Scholar
  50. Nakashima K, Yakabe Y, Yamazaki M, Abe H (2006) Effects of fasting and refeeding on expression of atrogin-1 and Akt/FOXO signaling pathway in skeletal muscle of chicks. Biosci Biotechnol Biochem 70:2775–2778. doi:10.1271/bbb.60274 PubMedCrossRefGoogle Scholar
  51. Navé BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344(Pt 2):427–431. doi:10.1042/0264-6021:3440427 PubMedCrossRefGoogle Scholar
  52. Noguchi S, Yasui Y, Iwasaki J, Kumazaki M, Yamada N, Naito S, Akao Y (2013) Replacement treatment with microRNA-143 and -145 induces synergistic inhibition of the growth of human bladder cancer cells by regulating PI3K/Akt and MAPK signaling pathways. Cancer Lett 328:353–361. doi:10.1016/j.canlet.2012.10.017 PubMedCrossRefGoogle Scholar
  53. Oliveira EM, Sasaki MS, Cerêncio M, Baraúna VG, Krieger JE (2009) Local reninangiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study. J Renin Angiotensin Aldosterone Syst 10:15–23. doi:10.1177/1470320309102304 PubMedCrossRefGoogle Scholar
  54. Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, Backx PH (2004) The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37:449–471. doi:10.1016/j.yjmcc.2004.05.015 PubMedCrossRefGoogle Scholar
  55. Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD (2007) Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci USA 104:14074–14079. doi:10.1073/pnas.0610906104 PubMedCrossRefGoogle Scholar
  56. Qiang R, Wang F, Shi LY, Liu M, Chen S, Wan HY, Li YX, Li X, Gao SY, Sun BC, Tang H (2011) Plexin-B1 is a target of miR-214 in cervical cancer and promotes the growth and invasion of HeLa cells. Int J Biochem Cell Biol 43:632–641. doi:10.1016/j.biocel.2011.01.002 PubMedCrossRefGoogle Scholar
  57. Sachdeva M, Liu Q, Cao J, Lu Z, Mo YY (2012) Negative regulation of miR-145 by C/EBP-β through the Akt pathway in cancer cells. Nucleic Acids Res 40:6683–6692. doi:10.1093/nar/gks324 PubMedCrossRefGoogle Scholar
  58. Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103:253–262. doi:10.1016/S0092-8674(00)00117-3 PubMedCrossRefGoogle Scholar
  59. Shao J, Yamashita H, Qiao L, Friedman JE (2000) Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. J Endocrinol 167:107–115. doi:10.1677/joe.0.1670107 PubMedCrossRefGoogle Scholar
  60. Shen WH, Chen Z, Shi S, Chen H, Zhu W, Penner A, Bu G, Li W, Boyle DW, Rubart M, Field LJ, Abraham R, Liechty EA, Shou W (2008) Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function. J Biol Chem 283:13842–13849. doi:10.1074/jbc.M801510200 PubMedCrossRefGoogle Scholar
  61. Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S (2002) Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 22:2799–2809. doi:10.1128/MCB.22.8.2799-2809 PubMedCrossRefGoogle Scholar
  62. Shioi T, McMullen JR, Tarnavski O, Converso K, Sherwood MC, Manning WJ, Izumo S (2003) Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107:1664–1670. doi:10.1161/01.CIR.0000057979.36322.88 PubMedCrossRefGoogle Scholar
  63. Soci UP, Fernandes T, Hashimoto NY, Mota GF, Amadeu MA, Rosa KT, Irigoyen MC, Phillips MI, Oliveira EM (2011) MicroRNAs 29 are involved in the improvement of ventricular compliance promoted by aerobic exercise training in rats. Physiol Genomics 43:665–673. doi:10.1152/physiolgenomics.00145.2010 PubMedCrossRefGoogle Scholar
  64. Soesanto W, Lin HY, Hu E, Lefler S, Litwin SE, Sena S, Abel ED, Symons JD, Jalili T (2009) Mammalian target of rapamycin is a critical regulator of cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 54:1321–1327. doi:10.1161/HYPERTENSIONAHA.109.138818 PubMedCrossRefGoogle Scholar
  65. Song X, Kusakari Y, Xiao CY, Kinsella SD, Rosenberg MA, Scherrer-Crosbie M, Hara K, Rosenzweig A, Matsui T (2010) mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol 299:C1256–C1266. doi:10.1152/ajpcell.00338.2010 PubMedCrossRefGoogle Scholar
  66. Sugden PH, Clerk A (1998) “Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 24:345–352. doi:10.1161/01.RES.83.4.345 CrossRefGoogle Scholar
  67. Tatsuguchi M, Seok HY, Callis TE, Thomson JM, Chen JF, Newman M, Rojas M, Hammond SM, Wang DZ (2007) Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol 42:1137–1141. doi:10.1016/j.yjmcc.2007.04.004 PubMedCrossRefGoogle Scholar
  68. Uziel T, Karginov FV, Xie S, Parker JS, Wang YD, Gajjar A, He L, Ellison D, Gilbertson RJ, Hannon G, Roussel MF (2009) The miR-17–92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci USA 106:2812–2817. doi:10.1073/pnas.0809579106 PubMedCrossRefGoogle Scholar
  69. Van Rooij E, Olson EN (2007) Micro RNAs: powerful new regulators of heart disease and provocative therapeutic agents. J Clin Invest 117:2369–2376. doi:10.1172/JCI33099 PubMedCrossRefGoogle Scholar
  70. Van Rooij E, Marshall WS, Olson EN (2008) Toward microRNA-based therapeutics for heart disease: the sense in antisense. Circ Res 103:919–928. doi:10.1161/CIRCRESAHA.108.183426 PubMedCrossRefGoogle Scholar
  71. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22:267–272. doi:10.1016/S0968-0004(97)01061-X PubMedCrossRefGoogle Scholar
  72. Vendelbo MH, Clasen BF, Treebak JT, Møller L, Krusenstjerna- Hafstrøm T, Madsen M, Nielsen TS, Stødkilde-Jørgensen H, Pedersen SB, Jørgensen JO, Goodyear LJ, Wojtaszewski JF, Møller N, Jessen N (2012) Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle. Am J Physiol Endocrinol Metab 302:E190–E200. doi:10.1152/ajpendo.00207.2011 PubMedCrossRefGoogle Scholar
  73. Wang RH, He JP, Su ML, Luo J, Xu M, Du XD, Chen HZ, Wang WJ, Wang Y, Zhang N, Zhao BX, Zhao WX, Shan ZG, Han JH, Chang CS, Wu Q (2013) The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signaling. EMBO Mol Med 5:137–148. doi:10.1002/emmm.201201369 PubMedCrossRefGoogle Scholar
  74. Wijesekara N, Konrad D, Eweida M, Jefferies C, Liadis N, Giacca A, Crackower M, Suzuki A, Mak TW, Kahn CR, Klip A, Woo M (2005) Muscle-specific Pten deletion protects against insulin resistance and diabetes. Mol Cell Biol 25:1135–1145. doi:10.1128/MCB.25.3.1135-1145.2005 PubMedCrossRefGoogle Scholar
  75. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484. doi:10.1016/j.cell.2006.01.016 PubMedCrossRefGoogle Scholar
  76. Xu XD, Song XW, Li Q, Wang GK, Jing Q, Qin YW (2012) Attenuation of microRNA-22 derepressed PTEN to effectively protect rat cardiomyocytes from hypertrophy. J Cell Physiol 227:1391–1398. doi:10.1002/jcp.22852 PubMedCrossRefGoogle Scholar
  77. Yang Q, Guan KL (2007) Expanding mTOR signaling. Cell Res 17:666–681. doi:10.1038/cr.2007.64 PubMedCrossRefGoogle Scholar
  78. Zhang J, Jima DD, Jacobs C, Fischer R, Gottwein E, Huang G, Lugar PL, Lagoo AS, Rizzieri DA, Friedman DR, Weinberg JB, Lipsky PE, Dave SS (2009) Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood 113:4586–4594. doi:10.1182/blood-2008-09-178186 PubMedCrossRefGoogle Scholar
  79. Zhang D, Contu R, Latronico MV, Zhang J, Rizzi R, Catalucci D, Miyamoto S, Huang K, Ceci M, Gu Y, Dalton ND, Peterson KL, Guan KL, Brown JH, Chen J, Sonenberg N, Condorelli G (2010) MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 120:2805–2816. doi:10.1172/JCI43008 PubMedCrossRefGoogle Scholar
  80. Zhang LY, Ho-Fun Lee V, Wong AM, Kwong DL, Zhu YH, Dong SS, Kong KL, Chen J, Tsao SW, Guan XY, Fu L (2013) microRNA-144 promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma through repression of PTEN. Carcinogenesis 34:454–463. doi:10.1093/carcin/bgs346 PubMedCrossRefGoogle Scholar
  81. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35. doi:10.1038/nrm3025 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Zhichao Ma
    • 1
  • Jie Qi
    • 1
  • Shuai Meng
    • 1
  • Baoju Wen
    • 1
  • Jun Zhang
    • 1
  1. 1.Physical Education CollegeYangzhou UniversityYangzhouChina

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