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Exercise for Cardiovascular Disease Prevention and Treatment pp 187–210Cite as

The IGF1-PI3K-Akt Signaling Pathway in Mediating Exercise-Induced Cardiac Hypertrophy and Protection

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1000))

Abstract

Regular physical activity or exercise training can lead to heart enlargement known as cardiac hypertrophy. Cardiac hypertrophy is broadly defined as an increase in heart mass. In adults, cardiac hypertrophy is often considered a poor prognostic sign because it often progresses to heart failure. Heart enlargement in a setting of cardiac disease is referred to as pathological cardiac hypertrophy and is typically characterized by cell death and depressed cardiac function. By contrast, physiological cardiac hypertrophy, as occurs in response to chronic exercise training (i.e. the ‘athlete’s heart’), is associated with normal or enhanced cardiac function. The following chapter describes the morphologically distinct types of heart growth, and the key role of the insulin-like growth factor 1 (IGF1) – phosphoinositide 3-kinase (PI3K)-Akt signaling pathway in regulating exercise-induced physiological cardiac hypertrophy and cardiac protection. Finally we summarize therapeutic approaches that target the IGF1-PI3K-Akt signaling pathway which are showing promise in preclinical models of heart disease.

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References

  1. Zak R (1984) In: Growth of the heart in health and disease. Raven Press, New York, pp 1–24, 131–185, 381–420

    Google Scholar 

  2. Sugden PH, Clerk A (1998) Cellular mechanisms of cardiac hypertrophy. J Mol Med 76(11):725–746

    Article  CAS  PubMed  Google Scholar 

  3. Cooper G (1987) Cardiocyte adaptation to chronically altered load. Annu Rev Physiol 49:501–518

    Article  CAS  PubMed  Google Scholar 

  4. Hunter JJ, Chien KR (1999) Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341(17):1276–1283

    Article  CAS  PubMed  Google Scholar 

  5. Levy D, Garrison RJ, Savage DD et al (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322(22):1561–1566

    Article  CAS  PubMed  Google Scholar 

  6. Barker WH, Mullooly JP, Getchell W (2006) Changing incidence and survival for heart failure in a well-defined older population, 1970–1974 and 1990–1994. Circulation 113(6):799–805

    Article  PubMed  Google Scholar 

  7. Clark RA, McLennan S, Dawson A et al (2004) Uncovering a hidden epidemic: a study of the current burden of heart failure in Australia. Heart Lung Circ 13(3):266–273

    Article  PubMed  Google Scholar 

  8. Wei X, Liu X, Rosenzweig A (2015) What do we know about the cardiac benefits of exercise? Trends Cardiovasc Med 25(6):529–536

    Article  CAS  PubMed  Google Scholar 

  9. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr et al (1989) Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 262(17):2395–2401

    Article  CAS  PubMed  Google Scholar 

  10. Kodama S, Saito K, Tanaka S et al (2009) Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 301(19):2024–2035

    Article  CAS  PubMed  Google Scholar 

  11. Lee DC, Sui X, Artero EG et al (2011) Long-term effects of changes in cardiorespiratory fitness and body mass index on all-cause and cardiovascular disease mortality in men: the Aerobics Center Longitudinal Study. Circulation 124(23):2483–2490

    Article  PubMed  PubMed Central  Google Scholar 

  12. Soonpaa MH, Kim KK, Pajak L et al (1996) Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Phys 271(5 Pt 2):H2183–H2189

    CAS  Google Scholar 

  13. McMullen JR, Shioi T, Zhang L et al (2003) Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci U S A 100(21):12355–12360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bernardo BC, Weeks KL, Pretorius L et al (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128(1):191–227

    Article  CAS  PubMed  Google Scholar 

  15. Weber KT, Brilla CG, Janicki JS (1993) Myocardial fibrosis: functional significance and regulatory factors. Cardiovasc Res 27(3):341–348

    Article  CAS  PubMed  Google Scholar 

  16. Cohn JN, Bristow MR, Chien KR et al (1997) Report of the national heart, lung, and blood institute special emphasis panel on heart failure research. Circulation 95(4):766–770

    Article  CAS  PubMed  Google Scholar 

  17. Hudlicka O, Brown M, Egginton S (1992) Angiogenesis in skeletal and cardiac muscle. Physiol Rev 72(2):369–417

    Article  CAS  PubMed  Google Scholar 

  18. Schaible TF, Scheuer J (1984) Response of the heart to exercise training. In: Zak R (ed) Growth of the heart in health and disease. Raven Press, New York

    Google Scholar 

  19. Ferrans VJ (1984) Cardiac hypertrophy: morphological aspects. In: Zak R (ed) Growth of the heart in health and disease. Raven Press, New York, pp 187–239

    Google Scholar 

  20. Fagard RH (1997) Impact of different sports and training on cardiac structure and function. Cardiol Clin 15(3):397–412

    Article  CAS  PubMed  Google Scholar 

  21. Chien KR, Knowlton KU, Zhu H et al (1991) Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J 5(15):3037–3046

    CAS  PubMed  Google Scholar 

  22. Izumo S, Nadal-Ginard B, Mahdavi V (1988) Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci U S A 85(2):339–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. MacLellan WR, Schneider MD (2000) Genetic dissection of cardiac growth control pathways. Annu Rev Physiol 62:289–319

    Article  CAS  PubMed  Google Scholar 

  24. Gunasinghe SK, Spinale FG (2004) Myocardial basis for heart failure: role of the cardiac interstitium. In: Mann DL (ed) Heart Failure. Saunders, Philadelphia, pp 57–70

    Google Scholar 

  25. Molkentin JD, Dorn IG 2nd (2001) Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol 63:391–426

    Article  CAS  PubMed  Google Scholar 

  26. Frey N, Olson EN (2003) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79

    Article  CAS  PubMed  Google Scholar 

  27. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7(8):589–600

    Article  CAS  PubMed  Google Scholar 

  28. Tham YK, Bernardo BC, Ooi JY et al (2015) Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 89(9):1401–1438

    Article  CAS  PubMed  Google Scholar 

  29. Neri Serneri GG, Boddi M, Modesti PA et al (2001) Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circ Res 89(11):977–982

    Article  CAS  PubMed  Google Scholar 

  30. Zebrowska A, Gasior Z, Langfort J (2009) Serum IGF-I and hormonal responses to incremental exercise in athletes with and without left ventricular hypertrophy. J Sports Sci Med 8(1):67–76

    PubMed  PubMed Central  Google Scholar 

  31. Zebrowska A, Waskiewicz Z, Zajac A et al (2013) IGF-1 response to arm exercise with eccentric and concentric muscle contractions in resistance-trained athletes with left ventricular hypertrophy. Int J Sports Med 34(2):116–122

    CAS  PubMed  Google Scholar 

  32. Kim J, Wende AR, Sena S et al (2008) Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol Endocrinol 22(11):2531–2543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McMullen JR, Shioi T, Huang W-Y et al (2004) The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway. J Biol Chem 279(6):4782–4793

    Article  CAS  PubMed  Google Scholar 

  34. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619

    Article  CAS  PubMed  Google Scholar 

  35. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M et al (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11(5):329–341

    Article  CAS  PubMed  Google Scholar 

  36. Antonetti DA, Algenstaedt P, Kahn CR (1996) Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol Cell Biol 16(5):2195–2203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kessler A, Uphues I, Ouwens DM et al (2001) Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. Am J Physiol Endocrinol Metab 280(1):E65–E74

    Article  CAS  PubMed  Google Scholar 

  38. Perrino C, Schroder JN, Lima B et al (2007) Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure. Circulation 116(22):2571–2579

    Article  CAS  PubMed  Google Scholar 

  39. Koziris LP, Hickson RC, Chatterton RT Jr et al (1999) Serum levels of total and free IGF-I and IGFBP-3 are increased and maintained in long-term training. J Appl Physiol 86(4):1436–1442

    Article  CAS  PubMed  Google Scholar 

  40. Kodama Y, Umemura Y, Nagasawa S et al (2000) Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6 J mice but not in C3H/Hej mice. Calcif Tissue Int 66(4):298–306

    Article  CAS  PubMed  Google Scholar 

  41. Yeh JK, Aloia JF, Chen M et al (1994) Effect of growth hormone administration and treadmill exercise on serum and skeletal IGF-I in rats. Am J Phys 266(1 Pt 1):E129–E135

    CAS  Google Scholar 

  42. Whitman M, Downes CP, Keeler M et al (1988) Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332(6165):644–646

    Article  CAS  PubMed  Google Scholar 

  43. James SR, Downes CP, Gigg R et al (1996) Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J 315(Pt 3):709–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Alessi DR, James SR, Downes CP et al (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7(4):261–269

    Article  CAS  PubMed  Google Scholar 

  45. Andjelkovic M, Alessi DR, Meier R et al (1997) Role of translocation in the activation and function of protein kinase B. J Biol Chem 272(50):31515–31524

    Article  CAS  PubMed  Google Scholar 

  46. Calleja V, Alcor D, Laguerre M et al (2007) Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. PLoS Biol 5(4):e95

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Luo J, McMullen JR, Sobkiw CL et al (2005) Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol Cell Biol 25(21):9491–9502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lu Z, Jiang Y-P, Wang W et al (2009) Loss of cardiac phosphoinositide 3-Kinase p110{alpha} results in contractile dysfunction. Circulation 120(4):318–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shioi T, Kang PM, Douglas PS et al (2000) The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J 19(11):2537–2548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yano N, Tseng A, Zhao TC et al (2008) Temporally controlled overexpression of cardiac-specific PI3Kalpha induces enhanced myocardial contractility–a new transgenic model. Am J Physiol Heart Circ Physiol 295(4):H1690–H1694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Perrino C, Naga Prasad SV, Mao L et al (2006) Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest 116(6):1547–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Weeks KL, Gao X, Du XJ et al (2012) Phosphoinositide 3-Kinase p110alpha is a master regulator of exercise-induced cardioprotection and pi3k gene therapy rescues cardiac dysfunction. Circ Heart Fail 5(4):523–534

    Article  CAS  PubMed  Google Scholar 

  53. Bostrom P, Mann N, Wu J et al (2010) C/EBPbeta controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143(7):1072–1083

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Rinaldi B, Corbi G, Boccuti S et al (2006) Exercise training affects age-induced changes in SOD and heat shock protein expression in rat heart. Exp Gerontol 41(8):764–770

    Article  CAS  PubMed  Google Scholar 

  55. Pinho CA, Tromm CB, Tavares AM et al (2012) Effects of different physical training protocols on ventricular oxidative stress parameters in infarction-induced rats. Life Sci 90(13–14):553–559

    Article  CAS  PubMed  Google Scholar 

  56. Hamilton KL, Powers SK, Sugiura T et al (2001) Short-term exercise training can improve myocardial tolerance to I/R without elevation in heat shock proteins. Am J Physiol Heart Circ Physiol 281(3):H1346–H1352

    Article  CAS  PubMed  Google Scholar 

  57. Chen T, Jin X, Crawford BH et al (2012) Cardioprotection from oxidative stress in the newborn heart by activation of PPARgamma is mediated by catalase. Free Radic Biol Med 53(2):208–215

    Article  PubMed  CAS  Google Scholar 

  58. Frederico MJ, Justo SL, Da Luz G et al (2009) Exercise training provides cardioprotection via a reduction in reactive oxygen species in rats submitted to myocardial infarction induced by isoproterenol. Free Radic Res 43(10):957–964

    Article  CAS  PubMed  Google Scholar 

  59. You W, Min X, Zhang X et al (2009) Cardiac-specific expression of heat shock protein 27 attenuated endotoxin-induced cardiac dysfunction and mortality in mice through a PI3K/Akt-dependent mechanism. Shock 32(1):108–117

    Article  CAS  PubMed  Google Scholar 

  60. Harris MB, Mitchell BM, Sood SG et al (2008) Increased nitric oxide synthase activity and Hsp90 association in skeletal muscle following chronic exercise. Eur J Appl Physiol 104(5):795–802

    Article  CAS  PubMed  Google Scholar 

  61. Kang YJ, Chen Y, Epstein PN (1996) Suppression of doxorubicin cardiotoxicity by overexpression of catalase in the heart of transgenic mice. J Biol Chem 271(21):12610–12616

    Article  CAS  PubMed  Google Scholar 

  62. Lin RC, Weeks KL, Gao XM et al (2010) PI3K(p110 alpha) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA. Arterioscler Thromb Vasc Biol 30(4):724–732

    Article  CAS  PubMed  Google Scholar 

  63. Sarbassov DD, Guertin DA, Ali SM et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  CAS  PubMed  Google Scholar 

  64. Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22(17):6247–6260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Alessi DR, Andjelkovic M, Caudwell B et al (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15(23):6541–6551

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Cross DA, Alessi DR, Cohen P et al (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789

    Article  CAS  PubMed  Google Scholar 

  67. Rosner M, Freilinger A, Hengstschlager M (2007) Akt regulates nuclear/cytoplasmic localization of tuberin. Oncogene 26(4):521–531

    Article  CAS  PubMed  Google Scholar 

  68. Manning BD, Tee AR, Logsdon MN et al (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10(1):151–162

    Article  CAS  PubMed  Google Scholar 

  69. Inoki K, Li Y, Zhu T et al (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4(9):648–657

    Article  CAS  PubMed  Google Scholar 

  70. Sussman MA, Volkers M, Fischer K et al (2011) Myocardial AKT: the omnipresent nexus. Physiol Rev 91(3):1023–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. DeBosch B, Treskov I, Lupu TS et al (2006) Akt1 is required for physiological cardiac growth. Circulation 113(17):2097–2104

    Article  CAS  PubMed  Google Scholar 

  72. Shioi T, McMullen JR, Kang PM et al (2002) Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 22(8):2799–2809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Matsui T, Li L, Wu JC et al (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277(25):22896–22901

    Article  CAS  PubMed  Google Scholar 

  74. Condorelli G, Drusco A, Stassi G et al (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A 99(19):12333–12338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shiraishi I, Melendez J, Ahn Y et al (2004) Nuclear targeting of Akt Enhances Kinase activity and survival of cardiomyocytes. Circ Res 94(7):884–891

    Article  CAS  PubMed  Google Scholar 

  76. Shiojima I, Walsh K (2006) Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 20(24):3347–3365

    Article  CAS  PubMed  Google Scholar 

  77. Kim YK, Kim SJ, Yatani A et al (2003) Mechanism of enhanced cardiac function in mice with hypertrophy induced by overexpressed Akt. J Biol Chem 278(48):47622–47628

    Article  CAS  PubMed  Google Scholar 

  78. Tsujita Y, Muraski J, Shiraishi I et al (2006) Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 103(32):11946–11951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shiojima I, Sato K, Izumiya Y et al (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115(8):2108–2118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yancopoulos GD, Davis S, Gale NW et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242–248

    Article  CAS  PubMed  Google Scholar 

  81. Riehle C, Wende AR, Zhu Y et al (2014) Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training. Mol Cell Biol 34(18):3450–3460

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Noh J, Wende AR, Olsen CD et al (2015) Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations. J Mol Cell Cardiol 89(Pt B):297–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Davis RT 3rd, Simon JN, Utter M et al (2015) Knockout of p21-activated kinase-1 attenuates exercise-induced cardiac remodelling through altered calcineurin signalling. Cardiovasc Res 108(3):335–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Volkers M, Toko H, Doroudgar S et al (2013) Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc Natl Acad Sci U S A 110(31):12661–12666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Danzi S, Klein I (2002) Thyroid hormone-regulated cardiac gene expression and cardiovascular disease. Thyroid 12(6):467–472

    Article  CAS  PubMed  Google Scholar 

  86. Dillmann WH (2002) Cellular action of thyroid hormone on the heart. Thyroid 12(6):447–452

    Article  CAS  PubMed  Google Scholar 

  87. Bedotto JB, Gay RG, Graham SD et al (1989) Cardiac hypertrophy induced by thyroid hormone is independent of loading conditions and beta adrenoceptor blockade. J Pharmacol Exp Ther 248(2):632–636

    CAS  PubMed  Google Scholar 

  88. Hudlicka O, Brown MD (1996) Postnatal growth of the heart and its blood vessels. J Vasc Res 33(4):266–287

    Article  CAS  PubMed  Google Scholar 

  89. Feldman T, Borow KM, Sarne DH et al (1986) Myocardial mechanics in hyperthyroidism: importance of left ventricular loading conditions, heart rate and contractile state. J Am Coll Cardiol 7(5):967–974

    Article  CAS  PubMed  Google Scholar 

  90. Forfar JC, Muir AL, Sawers SA et al (1982) Abnormal left ventricular function in hyperthyroidism: evidence for a possible reversible cardiomyopathy. N Engl J Med 307(19):1165–1170

    Article  CAS  PubMed  Google Scholar 

  91. Ching GW, Franklyn JA, Stallard TJ et al (1996) Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis. Heart 75(4):363–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lazar MA (1993) Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 14(2):184–193

    CAS  PubMed  Google Scholar 

  93. Mangelsdorf DJ, Thummel C, Beato M et al (1995) The nuclear receptor superfamily: the second decade. Cell 83(6):835–839

    Article  CAS  PubMed  Google Scholar 

  94. Lazar MA, Chin WW (1990) Nuclear thyroid hormone receptors. J Clin Invest 86(6):1777–1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Harvey CB, Williams GR (2002) Mechanism of thyroid hormone action. Thyroid 12(6):441–446

    Article  CAS  PubMed  Google Scholar 

  96. Izumo S, Nadal-Ginard B, Mahdavi V (1986) All members of the MHC multigene family respond to thyroid hormone in a highly tissue-specific manner. Science 231(4738):597–600

    Article  CAS  PubMed  Google Scholar 

  97. Rohrer D, Dillmann WH (1988) Thyroid hormone markedly increases the mRNA coding for sarcoplasmic reticulum Ca2 + −ATPase in the rat heart. J Biol Chem 263(15):6941–6944

    CAS  PubMed  Google Scholar 

  98. Nishiyama A, Kambe F, Kamiya K et al (1998) Effects of thyroid status on expression of voltage-gated potassium channels in rat left ventricle. Cardiovasc Res 40(2):343–351

    Article  CAS  PubMed  Google Scholar 

  99. Weiss RE, Korcarz C, Chassande O et al (2002) Thyroid hormone and cardiac function in mice deficient in thyroid hormone receptor-alpha or -beta: an echocardiograph study. Am J Physiol Endocrinol Metab 283(3):E428–E435

    Article  CAS  PubMed  Google Scholar 

  100. Bassett JH, Harvey CB, Williams GR (2003) Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol 213(1):1–11

    Article  CAS  PubMed  Google Scholar 

  101. Farach-Carson MC, Davis PJ (2003) Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways. J Pharmacol Exp Ther 307(3):839–845

    Article  CAS  PubMed  Google Scholar 

  102. Kenessey A, Ojamaa K (2006) Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem 281(30):20666–20672

    Article  CAS  PubMed  Google Scholar 

  103. McMullen JR, Amirahmadi F, Woodcock EA et al (2007) Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 104(2):612–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pretorius L, Du XJ, Woodcock EA et al (2009) Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am J Pathol 175(3):998–1009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ritchie RH, Love JE, Huynh K et al (2012) Enhanced phosphoinositide 3-kinase(p110alpha) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes. Diabetologia 55(12):3369–3381

    Article  CAS  PubMed  Google Scholar 

  106. Shioi T, McMullen JR, Tarnavski O et al (2003) Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107(12):1664–1670

    Article  CAS  PubMed  Google Scholar 

  107. McMullen JR, Sherwood MC, Tarnavski O et al (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109(24):3050–3055

    Article  CAS  PubMed  Google Scholar 

  108. Buerger A, Rozhitskaya O, Sherwood MC et al (2006) Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase. J Card Fail 12(5):392–398

    Article  CAS  PubMed  Google Scholar 

  109. Matsui T, Li L, del Monte F et al (1999) Adenoviral gene transfer of activated phosphatidylinositol 3′-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100(23):2373–2379

    Article  CAS  PubMed  Google Scholar 

  110. Matsui T, Tao J, del Monte F et al (2001) Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104(3):330–335

    Article  CAS  PubMed  Google Scholar 

  111. Yamashita K, Kajstura J, Discher DJ et al (2001) Reperfusion-activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin-like growth factor-1. Circ Res 88(6):609–614

    Article  CAS  PubMed  Google Scholar 

  112. Fujio Y, Nguyen T, Wencker D et al (2000) Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 101(6):660–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ceci M, Gallo P, Santonastasi M et al (2007) Cardiac-specific overexpression of E40K active Akt prevents pressure overload-induced heart failure in mice by increasing angiogenesis and reducing apoptosis. Cell Death Differ 14(5):1060–1062

    CAS  PubMed  Google Scholar 

  114. Araki S, Izumiya Y, Hanatani S et al (2012) Akt1-mediated skeletal muscle growth attenuates cardiac dysfunction and remodeling after experimental myocardial infarction. Circ Heart Fail 5(1):116–125

    Article  CAS  PubMed  Google Scholar 

  115. Cardone MH, Roy N, Stennicke HR et al (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282(5392):1318–1321

    Article  CAS  PubMed  Google Scholar 

  116. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13(22):2905–2927

    Article  CAS  PubMed  Google Scholar 

  117. Zha J, Harada H, Yang E et al (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87(4):619–628

    Article  CAS  PubMed  Google Scholar 

  118. Xing H, Zhang S, Weinheimer C et al (2000) 14-3-3 proteins block apoptosis and differentially regulate MAPK cascades. EMBO J 19(3):349–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gardai SJ, Hildeman DA, Frankel SK et al (2004) Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 279(20):21085–21095

    Article  CAS  PubMed  Google Scholar 

  120. Muraski JA, Rota M, Misao Y et al (2007) Pim-1 regulates cardiomyocyte survival downstream of Akt. Nat Med 13(12):1467–1475

    Article  CAS  PubMed  Google Scholar 

  121. Borillo GA, Mason M, Quijada P et al (2010) Pim-1 kinase protects mitochondrial integrity in cardiomyocytes. Circ Res 106(7):1265–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Li Q, Li B, Wang X et al (1997) Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 100(8):1991–1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Li B, Setoguchi M, Wang X et al (1999) Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart. Circ Res 84(9):1007–1019

    Article  CAS  PubMed  Google Scholar 

  124. Kajstura J, Fiordaliso F, Andreoli AM et al (2001) IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50(6):1414–1424

    Article  CAS  PubMed  Google Scholar 

  125. Welch S, Plank D, Witt S et al (2002) Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ Res 90(6):641–648

    Article  CAS  PubMed  Google Scholar 

  126. Huynh K, McMullen JR, Julius TL et al (2010) Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy. Diabetes 59(6):1512–1520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rigor DL, Bodyak N, Bae S et al (2009) Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase C{beta}2 in the regulation of physiologic developmental hypertrophy and heart function. Am J Physiol Heart Circ Physiol 296(3):H566–H572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kotlyar AA, Vered Z, Goldberg I et al (2001) Insulin-like growth factor I and II preserve myocardial structure in postinfarct swine. Heart 86(6):693–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Duerr RL, McKirnan MD, Gim RD et al (1996) Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation 93(12):2188–2196

    Article  CAS  PubMed  Google Scholar 

  130. Battler A, Hasdai D, Goldberg I et al (1995) Exogenous insulin-like growth factor II enhances post-infarction regional myocardial function in swine. Eur Heart J 16(12):1851–1859

    Article  CAS  PubMed  Google Scholar 

  131. Tajima M, Weinberg EO, Bartunek J et al (1999) Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation 99(1):127–134

    Article  CAS  PubMed  Google Scholar 

  132. Houck WV, Pan LC, Kribbs SB et al (1999) Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation 100(19):2003–2009

    Article  CAS  PubMed  Google Scholar 

  133. Jayasankar V, Bish LT, Pirolli TJ et al (2004) Local myocardial overexpression of growth hormone attenuates postinfarction remodeling and preserves cardiac function. Ann Thorac Surg 77(6):2122–2129. discussion 2129

    Article  PubMed  Google Scholar 

  134. Colao A, Marzullo P, Di Somma C et al (2001) Growth hormone and the heart. Clin Endocrinol 54(2):137–154

    Article  CAS  Google Scholar 

  135. Ren J, Samson WK, Sowers JR (1999) Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol 31(11):2049–2061

    Article  CAS  PubMed  Google Scholar 

  136. McMullen JR, Jay PY (2007) PI3K(p110alpha) Inhibitors as anti-cancer agents: minding the heart. Cell Cycle 6(8):910–913

    Article  CAS  PubMed  Google Scholar 

  137. Hajjar RJ (2013) Potential of gene therapy as a treatment for heart failure. J Clin Invest 123(1):53–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Gregorevic P, Blankinship MJ, Allen JM et al (2004) Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 10(8):828–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lin Z, Zhou P, von Gise A et al (2015) Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ Res 116(1):35–45

    Article  CAS  PubMed  Google Scholar 

  140. Cittadini A, Cuocolo A, Merola B et al (1994) Impaired cardiac performance in GH-deficient adults and its improvement after GH replacement. Am J Phys 267(2 Pt 1):E219–E225

    CAS  Google Scholar 

  141. Katare R, Caporali A, Zentilin L et al (2011) Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ Res 108(10):1238–1251

    Article  CAS  PubMed  Google Scholar 

  142. Sapra G, Tham YK, Cemerlang N et al (2014) The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nat Commun 5:5705

    Article  CAS  PubMed  Google Scholar 

  143. Moreira JB, Wohlwend M, Alves MN et al (2015) A small molecule activator of AKT does not reduce ischemic injury of the rat heart. J Transl Med 13:76

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Cordes KR, Srivastava D (2009) MicroRNA regulation of cardiovascular development. Circ Res 104(6):724–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sassen S, Miska EA, Caldas C (2008) MicroRNA – implications for cancer. Virchows Arch 452(1):1–10

    Article  CAS  PubMed  Google Scholar 

  146. Bernardo BC, Charchar FJ, Lin RC et al (2012) A MicroRNA guide for clinicians and basic scientists: background and experimental techniques. Heart Lung Circ 21(3):131–142

    Article  CAS  PubMed  Google Scholar 

  147. Bernardo BC, Ooi JY, Lin RC et al (2015) miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart. Future Med Chem 7(13):1771–1792

    Article  CAS  PubMed  Google Scholar 

  148. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  PubMed  Google Scholar 

  149. Chen J-F, Murchison EP, Tang R et al (2008) Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci U S A 105(6):2111–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. da Costa Martins PA, Bourajjaj M, Gladka M et al (2008) Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation 118(15):1567–1576

    Article  PubMed  CAS  Google Scholar 

  151. Tatsuguchi M, Seok HY, Callis TE et al (2007) Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol 42(6):1137–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Thum T, Galuppo P, Wolf C et al (2007) MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116(3):258–267

    Article  CAS  PubMed  Google Scholar 

  153. Small EM, Frost RJA, Olson EN (2010) MicroRNAs add a new dimension to cardiovascular disease. Circulation 121(8):1022–1032

    Article  PubMed  PubMed Central  Google Scholar 

  154. Thum T, Gross C, Fiedler J et al (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456(7224):980–984

    Article  CAS  PubMed  Google Scholar 

  155. van Rooij E, Sutherland LB, Thatcher JE et al (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A 105(35):13027–13032

    Article  PubMed  PubMed Central  Google Scholar 

  156. Callis TE, Pandya K, Seok HY et al (2009) MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest 119(9):2772–2786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Care A, Catalucci D, Felicetti F et al (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13(5):613–618

    Article  CAS  PubMed  Google Scholar 

  158. Ooi JY, Bernardo BC, McMullen JR (2014) The therapeutic potential of miRNAs regulated in settings of physiological cardiac hypertrophy. Future Med Chem 6(2):205–222

    Article  CAS  PubMed  Google Scholar 

  159. Bernardo BC, Gao XM, Winbanks CE et al (2012) Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci U S A 109(43):17615–17620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bernardo BC, Gao XM, Tham YK et al (2014) Silencing of miR-34a attenuates cardiac dysfunction in a setting of moderate, but not severe, hypertrophic cardiomyopathy. PLoS One 9(2):e90337

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Bernardo BC, Nguyen SS, Winbanks CE et al (2014) Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. FASEB J 28(12):5097–5110

    Article  CAS  PubMed  Google Scholar 

  162. Bernardo BC, Nguyen SS, Gao XM et al (2016) Inhibition of miR-154 protects against cardiac dysfunction and fibrosis in a mouse model of pressure overload. Sci Rep 6:22442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Bernardo BC, Ooi JYY, Matsumoto A et al (2016) Sex differences in response to miRNA-34a therapy in mouse models of cardiac disease: identification of sex-, disease- and treatment-regulated miRNAs. J Physiol 594(20):5959–5974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Wisloff U, Stoylen A, Loennechen JP et al (2007) Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation 115(24):3086–3094

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Baker Heart & Diabetes Institute, P.O. Box 6492, Melbourne, VIC, 3004, Australia

    Kate L. Weeks, Bianca C. Bernardo, Jenny Y. Y. Ooi, Natalie L. Patterson & Julie R. McMullen

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  1. Kate L. Weeks
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  2. Bianca C. Bernardo
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  3. Jenny Y. Y. Ooi
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  4. Natalie L. Patterson
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  5. Julie R. McMullen
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Correspondence to Kate L. Weeks or Julie R. McMullen .

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  1. Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China

    Junjie Xiao

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Weeks, K.L., Bernardo, B.C., Ooi, J.Y.Y., Patterson, N.L., McMullen, J.R. (2017). The IGF1-PI3K-Akt Signaling Pathway in Mediating Exercise-Induced Cardiac Hypertrophy and Protection. In: Xiao, J. (eds) Exercise for Cardiovascular Disease Prevention and Treatment. Advances in Experimental Medicine and Biology, vol 1000. Springer, Singapore. https://doi.org/10.1007/978-981-10-4304-8_12

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