Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular basis of physiological heart growth: fundamental concepts and new players

Key Points

  • Physiological hypertrophy is an adaptive form of cardiac hypertrophy that does not lead to heart disease in healthy individuals.

  • This cardiac growth maintains or augments cardiac function and increases angiogenesis and metabolism. Physiological hypertrophy does not promote fibrotic remodelling or cardiomyocyte death.

  • Physiological hypertrophy is initiated by specific hormones (triiodothyronine, insulin, insulin-like growth factor 1 and vascular endothelial growth factor) or stretch (loading), which activate a restricted number of intracellular signalling pathways (PI3K, AKT, mTOR and ERK1/2).

  • Metabolic reprogramming governed by AMP-activated protein kinase (AMPK) is essential for adaptive cardiac hypertrophy.

  • Exercise induced hypertrophy causes a downregulation of CCAAT/enhancer binding protein-β and the transcription of an exercise-specific gene set.

  • Intermittent PI3K, AKT, ERK1/2 or AMPK activation promotes the activation of a physiological hypertrophic programme to maintain or augment function, thus antagonizing pathological conditions.


The heart hypertrophies in response to developmental signals as well as increased workload. Although adult-onset hypertrophy can ultimately lead to disease, cardiac hypertrophy is not necessarily maladaptive and can even be beneficial. Progress has been made in our understanding of the structural and molecular characteristics of physiological cardiac hypertrophy, as well as of the endocrine effectors and associated signalling pathways that regulate it. Physiological hypertrophy is initiated by finite signals, which include growth hormones (such as thyroid hormone, insulin, insulin-like growth factor 1 and vascular endothelial growth factor) and mechanical forces that converge on a limited number of intracellular signalling pathways (such as PI3K, AKT, AMP-activated protein kinase and mTOR) to affect gene transcription, protein translation and metabolism. Harnessing adaptive signalling mediators to reinvigorate the diseased heart could have important medical ramifications.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Physiological hypertrophy signalling pathways.
Figure 2: Stretch-mechanosensing in the initiation of physiological hypertrophy.


  1. 1

    Bernardo, B. C., Weeks, K. L., Pretorius, L. & McMullen, J. R. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol. Ther. 128, 191–227 (2010).

    CAS  PubMed  Google Scholar 

  2. 2

    Heineke, J. & Molkentin, J. D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nature Rev. Mol. Cell Biol. 7, 589–600 (2006).

    CAS  Google Scholar 

  3. 3

    Van Berlo, J. H., Maillet, M. & Molkentin, J. D. Signaling effectors underlying pathologic growth and remodeling of the heart. J. Clin. Invest. (in the press).

  4. 4

    Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Kajstura, J. et al. Cardiomyogenesis in the aging and failing human heart. Circulation 126, 1869–1881 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Dorn, G. W. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 49, 962–970 (2007).

    CAS  PubMed  Google Scholar 

  7. 7

    Porrello, E. R., Widdop, R. E. & Delbridge, L. M. Early origins of cardiac hypertrophy: does cardiomyocyte attrition programme for pathological 'catch-up' growth of the heart? Clin. Exp. Pharmacol. Physiol. 35, 1358–1364 (2008).

    CAS  PubMed  Google Scholar 

  8. 8

    Hopkins, S. F. Jr, McCutcheon, E. P. & Wekstein, D. R. Postnatal changes in rat ventricular function. Circ. Res. 32, 685–691 (1973).

    PubMed  Google Scholar 

  9. 9

    Clubb, F. J. Jr & Bishop, S. P. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab. Invest. 50, 571–577 (1984).

    PubMed  Google Scholar 

  10. 10

    Eghbali, M., Wang, Y., Toro, L. & Stefani, E. Heart hypertrophy during pregnancy: a better functioning heart? Trends Cardiovasc. Med. 16, 285–291 (2006).

    PubMed  Google Scholar 

  11. 11

    Winsor, T. & Beckner, G. Hypertrophy of the heart; electrocardiographic distinction between physiologic and pathologic enlargement. Calif. Med. 82, 151–158 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Henschen, S. Skilanglauf and skiwettlauf: ein medizinische sportstudie. Mitt. Med. Klin. Uppsala 2, 15–18 (1899).

    Google Scholar 

  13. 13

    Nishimura, T., Yamada, Y. & Kawai, C. Echocardiographic evaluation of long-term effects of exercise on left ventricular hypertrophy and function in professional bicyclists. Circulation 61, 832–840 (1980).

    CAS  PubMed  Google Scholar 

  14. 14

    Sugishita, Y., Koseki, S., Matsuda, M., Yamaguchi, T. & Ito, I. Myocardial mechanics of athletic hearts in comparison with diseased hearts. Am. Heart J. 105, 273–280 (1983).

    CAS  PubMed  Google Scholar 

  15. 15

    Dickhuth, H. H., Reindell, H., Lehmann, M. & Keul, J. [Capacity for regression of the athletic heart]. Z. Kardiol. 74 (Suppl. 7), 135–143 (1985).

    PubMed  Google Scholar 

  16. 16

    Schannwell, C. M. et al. Left ventricular hypertrophy and diastolic dysfunction in healthy pregnant women. Cardiology 97, 73–78 (2002).

    PubMed  Google Scholar 

  17. 17

    Janz, K. F., Dawson, J. D. & Mahoney, L. T. Predicting heart growth during puberty: The Muscatine Study. Pediatrics 105, e63 (2000).

    CAS  PubMed  Google Scholar 

  18. 18

    Hew, K. W. & Keller, K. A. Postnatal anatomical and functional development of the heart: a species comparison. Birth Defects Res. B. Dev. Reprod. Toxicol. 68, 309–320 (2003).

    CAS  PubMed  Google Scholar 

  19. 19

    Pluim, B. M., Zwinderman, A. H., van der Laarse, A. & van der Wall, E. E. The athlete's heart. A meta-analysis of cardiac structure and function. Circulation 101, 336–344 (2000).

    CAS  PubMed  Google Scholar 

  20. 20

    Ehsani, A. A., Hagberg, J. M. & Hickson, R. C. Rapid changes in left ventricular dimensions and mass in response to physical conditioning and deconditioning. Am. J. Cardiol. 42, 52–56 (1978).

    CAS  PubMed  Google Scholar 

  21. 21

    Maron, B. J., Pelliccia, A., Spataro, A. & Granata, M. Reduction in left ventricular wall thickness after deconditioning in highly trained Olympic athletes. Br. Heart J. 69, 125–128 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sarquella-Brugada, G. et al. Genetics of sudden cardiac death in children and young athletes. Cardiol. Young 24, 1–15 (2012).

    Google Scholar 

  23. 23

    Patten, I. S. et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485, 333–338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Heiss, H. W. et al. Studies on the regulation of myocardial blood flow in man. I.: Training effects on blood flow and metabolism of the healthy heart at rest and during standardized heavy exercise. Bas. Res. Cardiol. 71, 658–675 (1976).

    CAS  Google Scholar 

  25. 25

    Pelliccia, A. et al. Coronary arteries in physiological hypertrophy: echocardiographic evidence of increased proximal size in elite athletes. Int. J. Sports Med. 11, 120–126 (1990).

    CAS  PubMed  Google Scholar 

  26. 26

    Laughlin, M. H., Bowles, D. K. & Duncker, D. J. The coronary circulation in exercise training. Am. J. Physiol. Heart Circ. Physiol. 302, H10–H23 (2012).

    CAS  PubMed  Google Scholar 

  27. 27

    Lopaschuk, G. D. & Jaswal, J. S. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J. Cardiovasc. Pharmacol. 56, 130–140 (2010).

    CAS  PubMed  Google Scholar 

  28. 28

    Gertz, E. W., Wisneski, J. A., Stanley, W. C. & Neese, R. A. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J. Clin. Invest. 82, 2017–2025 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Abel, E. D. & Doenst, T. Mitochondrial adaptations to physiological versus pathological cardiac hypertrophy. Cardiovasc. Res. 90, 234–242 (2011). In-depth review of the mitochondrial adaptations to physiological or pathological cardiac hypertrophic signals. Describes how the distinct cardiac metabolic profiles associated with physiological and pathological hypertrophy are initiated by specific signalling pathways: PI3K, AMPK and PGC1α.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Wilkins, B. J. et al. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ. Res. 94, 110–118 (2004).

    CAS  PubMed  Google Scholar 

  31. 31

    Burgess, M. L. et al. Exercise- and hypertension-induced collagen changes are related to left ventricular function in rat hearts. Am. J. Physiol. 270, H151–H159 (1996).

    CAS  PubMed  Google Scholar 

  32. 32

    Jin, H. et al. Effects of exercise training on cardiac function, gene expression, and apoptosis in rats. Am. J. Physiol. Heart Circ. Physiol. 279, H2994–H3002 (2000).

    CAS  PubMed  Google Scholar 

  33. 33

    Neri Serneri, G. G. et al. Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circ. Res. 89, 977–982 (2001).

    CAS  PubMed  Google Scholar 

  34. 34

    Bellomo, D. et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86, e29–e35 (2000).

    CAS  PubMed  Google Scholar 

  35. 35

    Karpanen, T. et al. Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ. Res. 103, 1018–1026 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Bry, M. et al. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation 122, 1725–1733 (2010).

    CAS  PubMed  Google Scholar 

  37. 37

    Stubbe, P., Gatz, J., Heidemann, P., Muhlen, A. & Hesch, R. Thyroxine-binding globulin, triiodothyronine, thyroxine and thyrotropin in newborn infants and children. Horm. Metab. Res. 10, 58–61 (1978).

    CAS  PubMed  Google Scholar 

  38. 38

    Hadj-Sahraoui, N., Seugnet, I., Ghorbel, M. T. & Demeneix, B. Hypothyroidism prolongs mitotic activity in the post-natal mouse brain. Neurosci. Lett. 280, 79–82 (2000).

    CAS  PubMed  Google Scholar 

  39. 39

    Morkin, E. Regulation of myosin heavy chain genes in the heart. Circulation 87, 1451–1460 (1993).

    CAS  PubMed  Google Scholar 

  40. 40

    Arsanjani, R., McCarren, M., Bahl, J. J. & Goldman, S. Translational potential of thyroid hormone and its analogs. J. Mol. Cell. Cardiol. 51, 506–511 (2011).

    CAS  PubMed  Google Scholar 

  41. 41

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

    CAS  PubMed  Google Scholar 

  42. 42

    Kenessey, A., Sullivan, E. A. & Ojamaa, K. Nuclear localization of protein kinase C-α induces thyroid hormone receptor-α1 expression in the cardiomyocyte. Am. J. Physiol. Heart Circ. Physiol. 290, H381–H389 (2006).

    CAS  PubMed  Google Scholar 

  43. 43

    Belakavadi, M., Saunders, J., Weisleder, N., Raghava, P. S. & Fondell, J. D. Repression of cardiac phospholamban gene expression is mediated by thyroid hormone receptor-α1 and involves targeted covalent histone modifications. Endocrinology 151, 2946–2956 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Brownsey, R. W., Boone, A. N. & Allard, M. F. Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms. Cardiovasc. Res. 34, 3–24 (1997).

    CAS  PubMed  Google Scholar 

  45. 45

    Shiojima, I. & Walsh, K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev. 20, 3347–3365 (2006). Comprehensive review on the role of PI3K–AKT signalling pathways in regulating physiological cardiac hypertrophy, cardiac contractile function and coronary angiogenesis.

    CAS  PubMed  Google Scholar 

  46. 46

    Araki, E. et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190 (1994).

    CAS  Google Scholar 

  47. 47

    Burks, D. J. et al. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377–382 (2000).

    CAS  PubMed  Google Scholar 

  48. 48

    Belke, D. D. et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J. Clin. Invest. 109, 629–639 (2002). Shows that insulin signalling controls postnatal cardiac growth. Cardiomyocyte-specific IR knockout was shown to result in cardiomyocytes with a reduced volume, and postnatal contractile and metabolic switches were altered.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Hu, P. et al. Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload. Am. J. Physiol. Heart Circ. Physiol. 285, H1261–H1269 (2003).

    CAS  PubMed  Google Scholar 

  50. 50

    Sena, S. et al. Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction. J. Mol. Cell. Cardiol. 46, 910–918 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Boudina, S. et al. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 119, 1272–1283 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Efstratiadis, A. Genetics of mouse growth. Int. J. Dev. Biol. 42, 955–976 (1998).

    CAS  PubMed  Google Scholar 

  53. 53

    Sutton, J. & Lazarus, L. A. Growth hormone in exercise: comparison of physiological and pharmacological stimuli. J. Appl. Physiol. 41, 523–527 (1976).

    CAS  PubMed  Google Scholar 

  54. 54

    Baker, J., Liu, J. P., Robertson, E. J. & Efstratiadis, A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75, 73–82 (1993).

    CAS  PubMed  Google Scholar 

  55. 55

    Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993). References 54 and 55 show that IGF1 signalling is essential for postnatal growth.

    CAS  PubMed  Google Scholar 

  56. 56

    Reiss, K. et al. Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc. Natl Acad. Sci. USA 93, 8630–8635 (1996).

    CAS  PubMed  Google Scholar 

  57. 57

    Delaughter, M. C., Taffet, G. E., Fiorotto, M. L., Entman, M. L. & Schwartz, R. J. Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice. FASEB J. 13, 1923–1929 (1999).

    CAS  PubMed  Google Scholar 

  58. 58

    McMullen, J. R. et al. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110α) pathway. J. Biol. Chem. 279, 4782–4793 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Kim, J. et al. Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol. Endocrinol. 22, 2531–2543 (2008). In this study, IGF1R targeted deletion in adult cardiomyocytes did not result in any baseline hypertrophic phenotype in young mice. IGF1R-targeted hearts were resistant to exercise induced hypertrophy.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Moellendorf, S. et al. IGF-IR signaling attenuates the age-related decline of diastolic cardiac function. Am. J. Physiol. Endocrinol. Metab. 303, e213–e222 (2012).

    CAS  PubMed  Google Scholar 

  61. 61

    Patel, A. et al. Canonical TRP channels and mechanotransduction: from physiology to disease states. Pflugers Arch. 460, 571–581 (2010).

    CAS  PubMed  Google Scholar 

  62. 62

    Musarò, A., McCullagh, K. J., Naya, F. J., Olson, E. N. & Rosenthal, N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400, 581–585 (1999).

    PubMed  Google Scholar 

  63. 63

    Maroto, R. et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nature Cell Biol. 7, 179–185 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Spassova, M. A., Hewavitharana, T., Xu, W., Soboloff, J. & Gill, D. L. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc. Natl Acad. Sci. USA 103, 16586–16591 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Seth, M. et al. TRPC1 channels are critical for hypertrophic signaling in the heart. Circ. Res. 105, 1023–1030 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wu, X., Eder, P., Chang, B. & Molkentin, J. D. TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc. Natl Acad. Sci. USA 107, 7000–7005 (2010). This study, along with reference 65, showed that TRPC channels are necessary mediators of cardiac hypertrophy.

    CAS  PubMed  Google Scholar 

  67. 67

    Shai, S. Y. et al. Cardiac myocyte-specific excision of the β1 integrin gene results in myocardial fibrosis and cardiac failure. Circ. Res. 90, 458–464 (2002).

    CAS  PubMed  Google Scholar 

  68. 68

    Johnston, R. K. et al. β3 integrin-mediated ubiquitination activates survival signaling during myocardial hypertrophy. FASEB J. 23, 2759–2771 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Cox, L., Umans, L., Cornelis, F., Huylebroeck, D. & Zwijsen, A. A broken heart: a stretch too far: an overview of mouse models with mutations in stretch-sensor components. Int. J. Cardiol. 131, 33–44 (2008).

    PubMed  Google Scholar 

  70. 70

    Linke, W. A. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc. Res. 77, 637–648 (2008).

    CAS  Google Scholar 

  71. 71

    Herman, D. S. et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 366, 619–628 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Shioi, T. et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    McMullen, J. R. et al. Phosphoinositide 3-kinase(p110α) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc. Natl Acad. Sci. USA 100, 12355–12360 (2003). This study, along with reference 72, showed that PI3Kα regulates the physiological growth of the heart in gain and loss of function studies. PI3Kα activity controls exercise-induced physiological cardiac hypertrophy but not pathological hypertrophy.

    CAS  PubMed  Google Scholar 

  74. 74

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

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Lu, Z. et al. Loss of cardiac phosphoinositide 3-kinase p110α results in contractile dysfunction. Circulation 120, 318–325 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Crackower, M. A. et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737–749 (2002). This study showed that PTEN deletion in cardiomyocytes promotes heart growth at the organ and cellular level. Overexpression of dominant negative p110α downstream of PTEN normalizes the phenotype.

    CAS  PubMed  Google Scholar 

  77. 77

    McManus, E. J. et al. The in vivo role of PtdIns(3,4,5)P3 binding to PDK1 PH domain defined by knockin mutation. EMBO J. 23, 2071–2082 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Mora, A. et al. Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J. 22, 4666–4676 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Oudit, G. Y. et al. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J. Mol. Cell. Cardiol. 37, 449–471 (2004).

    CAS  PubMed  Google Scholar 

  80. 80

    Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).

    CAS  Google Scholar 

  81. 81

    Chen, W. S. et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 15, 2203–2208 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F. & Birnbaum, M. J. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349–38352 (2001).

    CAS  PubMed  Google Scholar 

  83. 83

    DeBosch, B. et al. Akt1 is required for physiological cardiac growth. Circulation 113, 2097–2104 (2006).

    CAS  PubMed  Google Scholar 

  84. 84

    Shioi, T. et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799–2809 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

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

    CAS  PubMed  Google Scholar 

  86. 86

    Condorelli, G. et al. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc. Natl Acad. Sci. USA 99, 12333–12338 (2002).

    CAS  PubMed  Google Scholar 

  87. 87

    Shiojima, I. et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest. 115, 2108–2118 (2005). Showed that conditional expression of AKT1 in the heart for 2 weeks induces a reversible physiological hypertrophy while sustained AKT1 expression for 6 weeks causes heart failure.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Shiraishi, I. et al. Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ. Res. 94, 884–891 (2004).

    CAS  PubMed  Google Scholar 

  89. 89

    Rota, M. et al. Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ. Res. 97, 1332–1341 (2005).

    CAS  PubMed  Google Scholar 

  90. 90

    Haq, S. et al. Glycogen synthase kinase-3β is a negative regulator of cardiomyocyte hypertrophy. J. Cell. Biol. 151, 117–130 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Antos, C. L. et al. Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 99, 907–912 (2002).

    CAS  PubMed  Google Scholar 

  92. 92

    Michael, A. et al. Glycogen synthase kinase-3β regulates growth, calcium homeostasis, and diastolic function in the heart. J. Biol. Chem. 279, 21383–21393 (2004).

    CAS  PubMed  Google Scholar 

  93. 93

    Skurk, C. et al. The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J. Biol. Chem. 280, 20814–20823 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Malhowski, A. J. et al. Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin. Hum. Mol. Genet. 20, 1290–1305 (2011). Showed that Tsc1 deletion results in lethal developmental and postnatal cardiac hypertrophy that is reversed by rapamycin treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Wang, Y. et al. Rheb activates protein synthesis and growth in adult rat ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 45, 812–820 (2008).

    CAS  PubMed  Google Scholar 

  96. 96

    Shen, W. H. et al. 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 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Zhang, D. et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J. Clin. Invest. 120, 2805–2816 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Shende, P. et al. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 123, 1073–1082 (2011). This study, along with reference 97, shows that cardiac-specific mTOR or RAPTOR ablation results in heart failure without an initial phase of hypertrophy.

    PubMed  Google Scholar 

  99. 99

    McMullen, J. R. et al. Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy. Mol. Cell. Biol. 24, 6231–6240 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Tsukada, J., Yoshida, Y., Kominato, Y. & Auron, P. E. The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine 54, 6–19 (2011).

    CAS  PubMed  Google Scholar 

  101. 101

    Bostrom, P. et al. C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143, 1072–1083 (2010). Shows that C/EBPβ is specifically downregulated by exercise training. C/EBPβ downregulation increases cardiomyocyte proliferation and leads to the transcription of genes specific to exercise.

    PubMed  PubMed Central  Google Scholar 

  102. 102

    Bueno, O. F. et al. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19, 6341–6350 (2000). Demonstrates that activation of MEK1–ERK1/2 signalling in the mouse heart induces a non-pathological form of compensated cardiac hypertrophy.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Lips, D. J. et al. MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 109, 1938–1941 (2004).

    CAS  PubMed  Google Scholar 

  104. 104

    Purcell, N. H. et al. 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 (2007).

    CAS  PubMed  Google Scholar 

  105. 105

    Kehat, I. et al. Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth. Circ. Res. 108, 176–183 (2011).

    CAS  PubMed  Google Scholar 

  106. 106

    Kehat, I. & Molkentin, J. D. Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann. NY Acad. Sci. 1188, 96–102 (2010).

    CAS  PubMed  Google Scholar 

  107. 107

    Horman, S., Beauloye, C., Vanoverschelde, J. L. & Bertrand, L. AMP-activated protein kinase in the control of cardiac metabolism and remodeling. Curr. Heart Fail. Rep. 9, 164–173 (2012).

    CAS  PubMed  Google Scholar 

  108. 108

    Shibata, R. et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nature Med. 10, 1384–1389 (2004).

    CAS  PubMed  Google Scholar 

  109. 109

    Zarrinpashneh, E. et al. AMPKα2 counteracts the development of cardiac hypertrophy induced by isoproterenol. Biochem. Biophys. Res. Commun. 376, 677–681 (2008).

    CAS  PubMed  Google Scholar 

  110. 110

    Zhang, P. et al. AMP activated protein kinase-α2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52, 918–924 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Sakamoto, K. et al. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKα2 but not AMPKα1. Am. J. Physiol. Endocrinol. Metab. 290, e780–e788 (2006).

    CAS  PubMed  Google Scholar 

  112. 112

    Ikeda, Y. et al. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J. Biol. Chem. 284, 35839–35849 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Gundewar, S. et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ. Res. 104, 403–411 (2009). Shows that metformin exerts its cardioprotective effects through AMPK activation.

    CAS  PubMed  Google Scholar 

  114. 114

    Maloyan, A. et al. Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy. Proc. Natl Acad. Sci. USA 104, 5995–6000 (2007).

    CAS  PubMed  Google Scholar 

  115. 115

    Konhilas, J. P. et al. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ. Res. 98, 540–548 (2006).

    CAS  PubMed  Google Scholar 

  116. 116

    Care, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613–618 (2007).

    CAS  Google Scholar 

  117. 117

    Fernandes, T. et al. Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126. Hypertension 59, 513–520 (2012).

    CAS  PubMed  Google Scholar 

  118. 118

    Porrello, E. R. et al. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ. Res. 109, 670–679 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Callis, T. E. et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J. Clin. Invest. 119, 2772–2786 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Nishi, H. et al. MicroRNA-27a regulates β cardiac myosin heavy chain gene expression by targeting thyroid hormone receptor β1 in neonatal rat ventricular myocytes. Mol. Cell. Biol. 31, 744–755 (2011).

    CAS  PubMed  Google Scholar 

Download references


This work was supported by grants from the US National Institutes of Health (J.D.M., J.H.v.B. and M.M.), and the Howard Hughes Medical Institute (J.D.M).

Author information



Corresponding author

Correspondence to Jeffery D. Molkentin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


Jeffery D. Molkentin's homepage



From the Greek mys (muscle) and kardia (heart). It is the thick middle muscular layer of the heart that contracts.

Valvular stenosis

Also called heart valve disease. Valvular stenosis occurs in response to stiffening, thickening, fusion or blockage of one or more valves of the heart. The heart comprises four valves: the mitral, aortic, tricuspid and pulmonic valves.

Transverse-tubule system

Also called the T-tubule system. A T-tubule is a deep invagination of the sarcolemma (cardiomyocyte plasma membrane) enriched in excitation–contraction coupling molecules. T-tubule system refers to the network of T-tubules within an adult cardiomyocyte.

Systolic function

The performance of the left ventricle during systole, which is the contraction of the heart. The best index of left ventricle systolic function is ejection fraction, which is calculated as the difference between end-diastolic and end-systolic left ventricle volume, divided by the end-diastolic left ventricle volume.

Diastolic function

The performance of the left ventricle during diastole, which is the relaxation of the heart and the filling of the ventricle.

Arrhythmogenic channelopathies

Genetic or acquired cardiac ion channel diseases. Ion channels (sodium, potassium and calcium channels) control the electrical activity of the heart. Abnormal electrical activity can lead to cardiac arrhythmias (irregular cardiac rhythm) and sudden death.


Inflammation of the heart caused by a viral or bacterial infection or an autoimmune disease. Myocarditis sometimes induces eccentric hypertrophy and heart failure.

Stretch–spring sensing

Translation of changes in the cardiomyocyte extracellular environment (stretch) and the sarcomeres elasticity (spring) into biochemical hypertrophic signals.


Specialized plasma membrane of a myocyte.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maillet, M., van Berlo, J. & Molkentin, J. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14, 38–48 (2013).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing