Skip to main content

Advertisement

SpringerLink
Log in

Mouse models of growth hormone deficiency

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Nearly one century of research using growth hormone deficient (GHD) mouse lines has contributed greatly toward our knowledge of growth hormone (GH), a pituitary-derived hormone that binds and signals through the GH receptor and affects many metabolic processes throughout life. Although delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, small body size, and glucose intolerance appear to be among the negative characteristics of these GHD mouse lines, these mice still consistently outlive their normal sized littermates. Furthermore, the absence of GH action in these mouse lines leads to enhanced insulin sensitivity (likely due to the lack of GH’s diabetogenic actions), delayed onset for a number of age-associated physiological declines (including cognition, cancer, and neuromusculoskeletal frailty), reduced cellular senescence, and ultimately, extended lifespan. In this review, we provide details about history, availability, growth, physiology, and aging of five commonly used GHD mouse lines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Availability of data and material

Not applicable.

References

  1. Snell GD. Dwarf, a new Mendelian recessive character of the house mouse. Proc Natl Acad Sci U S A. 1929;15:733–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schaible R, Gowen JW. A new dwarf mouse. Abstract. Genetics. 1961;46:896.

    Google Scholar 

  3. Eicher EM, Beamer WG. Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J Hered. 1976;67:87–91.

    Article  CAS  PubMed  Google Scholar 

  4. Alba M, Salvatori R. A mouse with targeted ablation of the growth hormone-releasing hormone gene: a new model of isolated growth hormone deficiency. Endocrinology. 2004;145:4134–43.

    Article  CAS  PubMed  Google Scholar 

  5. List EO, Berryman DE, Buchman M, Jensen EA, Funk K, Duran-Ortiz S, et al. GH knockout mice have increased subcutaneous adipose tissue with decreased fibrosis and enhanced insulin sensitivity. Endocrinology. 2019;160:1743–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li S, Crenshaw EB 3rd, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature. 1990;347:528–33.

    Article  CAS  PubMed  Google Scholar 

  7. Simmons DM, Voss JW, Ingraham HA, Holloway JM, Broide RS, Rosenfeld MG, et al. Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev. 1990;4:695–711.

    Article  CAS  PubMed  Google Scholar 

  8. Slabaugh MB, Lieberman ME, Rutledge JJ, Gorski J. Growth hormone and prolactin synthesis in normal and homozygous Snell and Ames dwarf mice. Endocrinology. 1981;109:1040–6.

    Article  CAS  PubMed  Google Scholar 

  9. Cheng, T. C., Beamer, W. G., Phillips, J. A., 3rd, Bartke, A., Mallonee, R. L., and Dowling, C. (1983) Etiology of growth hormone deficiency in little, Ames, and Snell dwarf mice, Endocrinology 113, 1669–1678.

  10. Wilson DB, Wyatt DP. Immunocytochemical effects of thyroxine stimulation on the adenohypophysis of dwarf (dw) mutant mice. Cell Tissue Res. 1993;274:579–85.

    Article  CAS  PubMed  Google Scholar 

  11. Nissley SP, Knazek RA, Wolff GL. Somatomedin activity in sera of genetically small mice. Horm Metab Res. 1980;12:158–64.

    Article  CAS  PubMed  Google Scholar 

  12. Brown-Borg HM, Bartke A. GH and IGF1: roles in energy metabolism of long-living GH mutant mice. J Gerontol A Biol Sci Med Sci. 2012;67:652–60.

    Article  PubMed  CAS  Google Scholar 

  13. Papaconstantinou J, Deford JH, Gerstner A, Hsieh CC, Boylston WH, Guigneaux MM, et al. Hepatic gene and protein expression of primary components of the IGF-I axis in long lived Snell dwarf mice. Mech Ageing Dev. 2005;126:692–704.

    Article  CAS  PubMed  Google Scholar 

  14. Lin C, Lin SC, Chang CP, Rosenfeld MG. Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth. Nature. 1992;360:765–8.

    Article  CAS  PubMed  Google Scholar 

  15. O'Hara BF, Bendotti C, Reeves RH, Oster-Granite ML, Coyle JT, Gearhart JD. Genetic mapping and analysis of somatostatin expression in Snell dwarf mice. Brain Res. 1988;464:283–92.

    CAS  PubMed  Google Scholar 

  16. Ward RD, Stone BM, Raetzman LT, Camper SA. Cell proliferation and vascularization in mouse models of pituitary hormone deficiency. Mol Endocrinol. 2006;20:1378–90.

    Article  CAS  PubMed  Google Scholar 

  17. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A. 2001;98:6736–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bartke A. The response of two types of dwarf mice to growth hormone, thyrotropin, and thyroxine. Gen Comp Endocrinol. 1965;5:418–26.

    Article  CAS  PubMed  Google Scholar 

  19. Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA. Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci. 2004;59:1244–50.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Brooks NL, Trent CM, Raetzsch CF, Flurkey K, Boysen G, Perfetti MT, et al. Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J Biol Chem. 2007;282:35069–77.

    Article  CAS  PubMed  Google Scholar 

  21. Stout MB, Tchkonia T, Pirtskhalava T, Palmer AK, List EO, Berryman DE, et al. Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY). 2014;6:575–86.

    Article  Google Scholar 

  22. Hochereau-de Reviers MT, de Reviers MM, Monet-Kuntz C, Perreau C, Fontaine I, Viguier-Martinez MC. Testicular growth and hormonal parameters in the male Snell dwarf mouse. Acta Endocrinol. 1987;115:399–405.

    Article  CAS  Google Scholar 

  23. Mustapha M, Fang Q, Gong TW, Dolan DF, Raphael Y, Camper SA, et al. Deafness and permanently reduced potassium channel gene expression and function in hypothyroid Pit1dw mutants. J Neurosci. 2009;29:1212–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Deol MS. Congenital deafness and hypothyroidism. Lancet. 1973;2:105–6.

    Article  CAS  PubMed  Google Scholar 

  25. Trotter WR. The association of deafness with thyroid dysfunction. Br Med Bull. 1960;16:92–8.

    Article  CAS  PubMed  Google Scholar 

  26. Sundaresan S, Kong JH, Fang Q, Salles FT, Wangsawihardja F, Ricci AJ, et al. Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses. Eur J Neurosci. 2016;43:148–61.

    Article  PubMed  Google Scholar 

  27. Sharlin DS, Ng L, Verrey F, Visser TJ, Liu Y, Olszewski RT, et al. Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters Slc16a2 (Mct8) and Slc16a10 (Mct10). Sci Rep. 2018;8:018–22553.

    Article  CAS  Google Scholar 

  28. Sundaresan S, Balasubbu S, Mustapha M. Thyroid hormone is required for the pruning of afferent type II spiral ganglion neurons in the mouse cochlea. Neuroscience. 2016;312:165–78.

    Article  CAS  PubMed  Google Scholar 

  29. Karolyi IJ, Dootz GA, Halsey K, Beyer L, Probst FJ, Johnson KR, et al. Dietary thyroid hormone replacement ameliorates hearing deficits in hypothyroid mice. Mamm Genome. 2007;18:596–608.

    Article  CAS  PubMed  Google Scholar 

  30. Stickland NC, Crook AR, Sutton CM. Effects of pituitary dwarfism in the mouse on fast and slow skeletal muscles. Acta Anat (Basel). 1994;151:245–9.

    Article  CAS  Google Scholar 

  31. Rader EP, Naimo MA, Ensey J, Baker BA. VCAM-1 upregulation accompanies muscle remodeling following resistance-type exercise in Snell dwarf (Pit1(dw/dw)) mice. Aging Cell. 2018;17:e12816.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Dumont F, Robert F, Bischoff P. T and B lymphocytes in pituitary dwarf Snell-Bagg mice. Immunology. 1979;38:23–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Montecino-Rodriguez E, Clark RG, Powell-Braxton L, Dorshkind K. Primary B cell development is impaired in mice with defects of the pituitary/thyroid axis. J Immunol. 1997;159:2712–9.

    CAS  PubMed  Google Scholar 

  34. Gala RR. Influence of thyroxine and thyroxine with growth hormone and prolactin on splenocyte subsets and on the expression of interleukin-2 and prolactin receptors on splenocyte subsets of Snell dwarf mice. Proc Soc Exp Biol Med. 1995;210:117–25.

    Article  CAS  PubMed  Google Scholar 

  35. Montecino-Rodriguez E, Clark R, Johnson A, Collins L, Dorshkind K. Defective B cell development in Snell dwarf (dw/dw) mice can be corrected by thyroxine treatment. J Immunol. 1996;157:3334–40.

    CAS  PubMed  Google Scholar 

  36. Cross RJ, Bryson JS, Roszman TL. Immunologic disparity in the hypopituitary dwarf mouse. J Immunol. 1992;148:1347–52.

    CAS  PubMed  Google Scholar 

  37. Flurkey K, Papaconstantinou J, Harrison DE. The Snell dwarf mutation Pit1(dw) can increase life span in mice. Mech Ageing Dev. 2002;123:121–30.

    Article  CAS  PubMed  Google Scholar 

  38. Bartke A, Brown-Borg H, Mattison J, Kinney B, Hauck S, Wright C. Prolonged longevity of hypopituitary dwarf mice. Exp Gerontol. 2001;36:21–8.

    Article  CAS  PubMed  Google Scholar 

  39. Dominick G, Berryman DE, List EO, Kopchick JJ, Li X, Miller RA, et al. Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice. Endocrinology. 2015;156:565–75.

    Article  PubMed  CAS  Google Scholar 

  40. Guevara-Aguirre J, Rosenbloom AL, Balasubramanian P, Teran E, Guevara-Aguirre M, Guevara C, et al. GH receptor deficiency in Ecuadorian adults is associated with obesity and enhanced insulin sensitivity. J Clin Endocrinol Metab. 2015;100:2589–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Drake JC, Bruns DR, Peelor FF 3rd, Biela LM, Miller RA, Miller BF, et al. Long-lived Snell dwarf mice display increased proteostatic mechanisms that are not dependent on decreased mTORC1 activity. Aging Cell. 2015;14:474–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dominick G, Bowman J, Li X, Miller RA, Garcia GG. mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell. 2017;16:52–60.

    Article  CAS  PubMed  Google Scholar 

  43. Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm. Mech Ageing Dev. 2002;123:1229–44.

    Article  CAS  PubMed  Google Scholar 

  44. Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse. Mech Ageing Dev. 2002;123:1245–55.

    Article  CAS  PubMed  Google Scholar 

  45. Meer MV, Podolskiy DI, Tyshkovskiy A, Gladyshev VN. A whole lifespan mouse multi-tissue DNA methylation clock. Elife. 2018;7.

  46. Madsen MA, Hsieh CC, Boylston WH, Flurkey K, Harrison D, Papaconstantinou J. Altered oxidative stress response of the long-lived Snell dwarf mouse. Biochem Biophys Res Commun. 2004;318:998–1005.

    Article  CAS  PubMed  Google Scholar 

  47. Hsieh CC, Papaconstantinou J. Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J. 2006;20:259–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sun LY, Steinbaugh MJ, Masternak MM, Bartke A, Miller RA. Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes. Free Radic Biol Med. 2009;47:1753–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Murakami S, Salmon A, Miller RA. Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J. 2003;17:1565–6.

    Article  CAS  PubMed  Google Scholar 

  50. Wang M, Miller RA. Fibroblasts from long-lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress. Aging Cell. 2012;11:668–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Page MM, Salmon AB, Leiser SF, Robb EL, Brown MF, Miller RA, et al. Mechanisms of stress resistance in Snell dwarf mouse fibroblasts: enhanced antioxidant and DNA base excision repair capacity, but no differences in mitochondrial metabolism. Free Radic Biol Med. 2009;46:1109–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leiser SF, Miller RA. Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol. 2010;30:871–84.

    Article  CAS  PubMed  Google Scholar 

  53. Tallaksen-Greene SJ, Sadagurski M, Zeng L, Mauch R, Perkins M, Banduseela VC, et al. Differential effects of delayed aging on phenotype and striatal pathology in a murine model of Huntington disease. J Neurosci. 2014;34:15658–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Alderman JM, Flurkey K, Brooks NL, Naik SB, Gutierrez JM, Srinivas U, et al. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp Gerontol. 2009;44:26–33.

    Article  CAS  PubMed  Google Scholar 

  55. Steinbaugh MJ, Sun LY, Bartke A, Miller RA. Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am J Physiol Endocrinol Metab. 2012;303:E488–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Perez Millan MI, Brinkmeier ML, Mortensen AH, Camper SA. PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells. Elife. 2016;5.

  57. Andersen B, Pearse RV 2nd, Jenne K, Sornson M, Lin SC, Bartke A, et al. The Ames dwarf gene is required for Pit-1 gene activation. Dev Biol. 1995;172:495–503.

    Article  CAS  PubMed  Google Scholar 

  58. Gage PJ, Roller ML, Saunders TL, Scarlett LM, Camper SA. Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion. Development. 1996;122:151–60.

    CAS  PubMed  Google Scholar 

  59. Gage PJ, Brinkmeier ML, Scarlett LM, Knapp LT, Camper SA, Mahon KA. The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. Mol Endocrinol. 1996;10:1570–81.

    CAS  PubMed  Google Scholar 

  60. Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O'Connell SM, et al. Pituitary lineage determination by the prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature. 1996;384:327–33.

    Article  CAS  PubMed  Google Scholar 

  61. Dasen JS, Martinez Barbera JP, Herman TS, Connell SO, Olson L, Ju B, et al. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 2001;15:3193–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Raetzman LT, Ward R, Camper SA. Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia. Development. 2002;129:4229–39.

    CAS  PubMed  Google Scholar 

  63. Kato Y, Murakami Y, Sohmiya M, Nishiki M. Regulation of human growth hormone secretion and its disorders. Intern Med. 2002;41:7–13.

    Article  CAS  PubMed  Google Scholar 

  64. Davis SW, Keisler JL, Perez-Millan MI, Schade V, Camper SA. All hormone-producing cell types of the pituitary intermediate and anterior lobes derive from Prop1-expressing progenitors. Endocrinology. 2016;157:1385–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bartke A. Histology of the anterior Hypophysis, Thyroid and Gonads of Two Types of Dwarf Mice. Anat Rec. 1964;149:225–35.

    Article  CAS  PubMed  Google Scholar 

  66. Ward RD, Raetzman LT, Suh H, Stone BM, Nasonkin IO, Camper SA. Role of PROP1 in pituitary gland growth. Mol Endocrinol. 2005;19:698–710.

    Article  CAS  PubMed  Google Scholar 

  67. Hurley DL, Wojtkiewicz PW, Phelps CJ. Growth hormone and Pit-1 mRNA detection using reverse transcription-polymerase chain reaction in adult and developing Ames dwarf mice. Recent Prog Horm Res. 1995;50:443–8.

    CAS  PubMed  Google Scholar 

  68. Bartke A, Goldman BD, Bex F, Dalterio S. Effects of prolactin (PRL) on pituitary and testicular function in mice with hereditary PRL deficiency. Endocrinology. 1977;101:1760–6.

    Article  CAS  PubMed  Google Scholar 

  69. Barkley MS, Bartke A, Gross DS, Sinha YN. Prolactin status of hereditary dwarf mice. Endocrinology. 1982;110:2088–96.

    Article  CAS  PubMed  Google Scholar 

  70. Phillips JA 3rd, Beamer WG, Bartke A. Analysis of growth hormone genes in mice with genetic defects of growth hormone expression. J Endocrinol. 1982;92:405–7.

    Article  CAS  PubMed  Google Scholar 

  71. Phelps CJ, Carlson SW, Vaccarella MY, Felten SY. Developmental assessment of hypothalamic tuberoinfundibular dopamine in prolactin-deficient dwarf mice. Endocrinology. 1993;132:2715–22.

    Article  CAS  PubMed  Google Scholar 

  72. Chandrashekar V, Bartke A. Induction of endogenous insulin-like growth factor-I secretion alters the hypothalamic-pituitary-testicular function in growth hormone-deficient adult dwarf mice. Biol Reprod. 1993;48:544–51.

    Article  CAS  PubMed  Google Scholar 

  73. Phelps CJ, Dalcik H, Endo H, Talamantes F, Hurley DL. Growth hormone-releasing hormone peptide and mRNA are overexpressed in GH-deficient Ames dwarf mice. Endocrinology. 1993;133:3034–7.

    Article  CAS  PubMed  Google Scholar 

  74. Gage PJ, Lossie AC, Scarlett LM, Lloyd RV, Camper SA. Ames dwarf mice exhibit somatotrope commitment but lack growth hormone-releasing factor response. Endocrinology. 1995;136:1161–7.

    Article  CAS  PubMed  Google Scholar 

  75. Phelps CJ. Pituitary hormones as neurotrophic signals: anomalous hypophysiotrophic neuron differentiation in hypopituitary dwarf mice. Proc Soc Exp Biol Med. 1994;206:6–23.

    Article  CAS  PubMed  Google Scholar 

  76. Hurley DL, Wee BE, Phelps CJ. Hypophysiotropic somatostatin expression during postnatal development in growth hormone-deficient Ames dwarf mice: mRNA in situ hybridization. Neuroendocrinology. 1997;65:98–106.

    Article  CAS  PubMed  Google Scholar 

  77. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature. 1996;384:33.

    Article  CAS  PubMed  Google Scholar 

  78. Borg KE, Brown-Borg HM, Bartke A. Assessment of the primary adrenal cortical and pancreatic hormone basal levels in relation to plasma glucose and age in the unstressed Ames dwarf mouse. Proc Soc Exp Biol Med. 1995;210:126–33.

    Article  CAS  PubMed  Google Scholar 

  79. Dominici FP, Hauck S, Argentino DP, Bartke A, Turyn D. Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice. J Endocrinol. 2002;173:81–94.

    Article  CAS  PubMed  Google Scholar 

  80. Dominici FP, Argentino DP, Bartke A, Turyn D. The dwarf mutation decreases high dose insulin responses in skeletal muscle, the opposite of effects in liver. Mech Ageing Dev. 2003;124:819–27.

    Article  CAS  PubMed  Google Scholar 

  81. Argentino DP, Dominici FP, Munoz MC, Al-Regaiey K, Bartke A, Turyn D. Effects of long-term caloric restriction on glucose homeostasis and on the first steps of the insulin signaling system in skeletal muscle of normal and Ames dwarf (Prop1df/Prop1df) mice. Exp Gerontol. 2005;40:27–35.

    Article  CAS  PubMed  Google Scholar 

  82. Brown-Borg HM, Rakoczy S. Metabolic adaptations to short-term every-other-day feeding in long-living Ames dwarf mice. Exp Gerontol. 2013;48:905–19.

    Article  CAS  PubMed  Google Scholar 

  83. Wang Z, Al-Regaiey KA, Masternak MM, Bartke A. Adipocytokines and lipid levels in Ames dwarf and calorie-restricted mice. J Gerontol A Biol Sci Med Sci. 2006;61:323–31.

    Article  PubMed  Google Scholar 

  84. Darcy J, McFadden S, Bartke A. Altered structure and function of adipose tissue in long-lived mice with growth hormone-related mutations. Adipocyte. 2017;6:69–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Menon V, Zhi X, Hossain T, Bartke A, Spong A, Gesing A, et al. The contribution of visceral fat to improved insulin signaling in Ames dwarf mice. Aging Cell. 2014;13:497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hill CM, Fang Y, Miquet JG, Sun LY, Masternak MM, Bartke A. Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure. Aging Cell. 2016;15:509–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hunter WS, Croson WB, Bartke A, Gentry MV, Meliska CJ. Low body temperature in long-lived Ames dwarf mice at rest and during stress. Physiol Behav. 1999;67:433–7.

    Article  CAS  PubMed  Google Scholar 

  88. Darcy J, McFadden S, Fang Y, Huber JA, Zhang C, Sun LY, et al. Brown adipose tissue function is enhanced in long-lived, Male Ames Dwarf Mice. Endocrinology. 2016;157:4744–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tang K, Bartke A, Gardiner CS, Wagner TE, Yun JS. Gonadotropin secretion, synthesis, and gene expression in human growth hormone transgenic mice and in Ames dwarf mice. Endocrinology. 1993;132:2518–24.

    Article  CAS  PubMed  Google Scholar 

  90. Nasonkin IO, Ward RD, Raetzman LT, Seasholtz AF, Saunders TL, Gillespie PJ, et al. Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice. Hum Mol Genet. 2004;13:2727–35.

    Article  CAS  PubMed  Google Scholar 

  91. Saccon TD, Moreira F, Cruz LA, Mondadori RG, Fang Y, Barros CC, et al. Ovarian aging and the activation of the primordial follicle reserve in the long-lived Ames dwarf and the short-lived bGH transgenic mice. Mol Cell Endocrinol. 2017;455:23–32.

    Article  CAS  PubMed  Google Scholar 

  92. Schneider A, Matkovich SJ, Saccon T, Victoria B, Spinel L, Lavasani M, et al. Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice. Mol Cell Endocrinol. 2017;439:328–36.

    Article  CAS  PubMed  Google Scholar 

  93. Villanua MA, Szary A, Esquifino AI, Bartke A. Thymostimulin effects on lymphoid organs in Ames dwarf mice. Acta Endocrinol. 1993;128:74–80.

    Article  CAS  Google Scholar 

  94. Hall MA, Bartke A, Martinko JM. Humoral immune response in mice over-expressing or deficient in growth hormone. Exp Biol Med (Maywood). 2002;227:535–44.

    Article  CAS  Google Scholar 

  95. Capitano ML, Chitteti BR, Cooper S, Srour EF, Bartke A, Broxmeyer HE. Ames hypopituitary dwarf mice demonstrate imbalanced myelopoiesis between bone marrow and spleen. Blood Cells Mol Dis. 2015;55:15–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang X, Darcy J, Cai C, Jin J, Bartke A, Cao D. Intestinal immunity in hypopituitary dwarf mice: effects of age. Aging (Albany NY). 2018;10:358–70.

    Article  CAS  Google Scholar 

  97. Brown-Borg HM. The somatotropic axis and longevity in mice. Am J Physiol Endocrinol Metab. 2015;309:E503–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS. Extending the lifespan of long-lived mice. Nature. 2001;414:412.

    Article  CAS  PubMed  Google Scholar 

  99. Barger JL, Walford RL, Weindruch R. The retardation of aging by caloric restriction: its significance in the transgenic era. Exp Gerontol. 2003;38:1343–51.

    Article  PubMed  Google Scholar 

  100. Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A. Genetic mouse models of extended lifespan. Exp Gerontol. 2003;38:1353–64.

    Article  CAS  PubMed  Google Scholar 

  101. Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J. 2010;24:5073–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Wilkes EH, Casado P, Rajeeve V, Cutillas PR. Kinase activity ranking using phosphoproteomics data (KARP) quantifies the contribution of protein kinases to the regulation of cell viability. Mol Cell Proteomics. 2017;16:1694–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Brown-Borg HM, Rakoczy SG. Catalase expression in delayed and premature aging mouse models. Exp Gerontol. 2000;35:199–212.

    Article  CAS  PubMed  Google Scholar 

  104. Romanick MA, Rakoczy SG, Brown-Borg HM. Long-lived Ames dwarf mouse exhibits increased antioxidant defense in skeletal muscle. Mech Ageing Dev. 2004;125:269–81.

    Article  CAS  PubMed  Google Scholar 

  105. Kennedy MA, Rakoczy SG, Brown-Borg HM. Long-living Ames dwarf mouse hepatocytes readily undergo apoptosis. Exp Gerontol. 2003;38:997–1008.

    Article  CAS  PubMed  Google Scholar 

  106. Brown-Borg HM, Rakoczy SG, Uthus EO. Growth hormone alters methionine and glutathione metabolism in Ames dwarf mice. Mech Ageing Dev. 2005;126:389–98.

    Article  CAS  PubMed  Google Scholar 

  107. Uthus EO, Brown-Borg HM. Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse. Mech Ageing Dev. 2006;127:444–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Uthus EO, Brown-Borg HM. Altered methionine metabolism in long living Ames dwarf mice. Exp Gerontol. 2003;38:491–8.

    Article  CAS  PubMed  Google Scholar 

  109. Brown-Borg HM, Rakoczy SG, Wonderlich JA, Rojanathammanee L, Kopchick JJ, Armstrong V, et al. Growth hormone signaling is necessary for lifespan extension by dietary methionine. Aging Cell. 2014;13:1019–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Brown-Borg HM, Rakoczy SG. Glutathione metabolism in long-living Ames dwarf mice. Exp Gerontol. 2005;40:115–20.

    Article  CAS  PubMed  Google Scholar 

  111. Choksi KB, Roberts LJ 2nd, DeFord JH, Rabek JP, Papaconstantinou J. Lower levels of F2-isoprostanes in serum and livers of long-lived Ames dwarf mice. Biochem Biophys Res Commun. 2007;364:761–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee C, Wan J, Miyazaki B, Fang Y, Guevara-Aguirre J, Yen K, et al. IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell. 2014;13:958–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA. Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab. 2005;289:E23–9.

    Article  CAS  PubMed  Google Scholar 

  114. Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, et al. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol. 2008;295:H1882–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kinney BA, Meliska CJ, Steger RW, Bartke A. Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm Behav. 2001;39:277–84.

    Article  CAS  PubMed  Google Scholar 

  116. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci. 2003;58:291–6.

    Article  PubMed  Google Scholar 

  117. Arum O, Rasche ZA, Rickman DJ, Bartke A. Prevention of neuromusculoskeletal frailty in slow-aging Ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction. PLoS One. 2013;8:e72255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kinney-Forshee BA, Kinney NE, Steger RW, Bartke A. Could a deficiency in growth hormone signaling be beneficial to the aging brain? Physiol Behav. 2004;80:589–94.

    Article  CAS  PubMed  Google Scholar 

  119. Ebadi M, Brown-Borg H, El Refaey H, Singh BB, Garrett S, Shavali S, et al. Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Brain Res Mol Brain Res. 2005;134:67–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sun LY, Evans MS, Hsieh J, Panici J, Bartke A. Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology. 2005;146:1138–44.

    Article  CAS  PubMed  Google Scholar 

  121. Sharma S, Rakoczy S, Dahlheimer K, Brown-Borg H. The hippocampus of Ames dwarf mice exhibits enhanced antioxidative defenses following kainic acid-induced oxidative stress. Exp Gerontol. 2010;45:936–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Basu R, Kopchick JJ. The effects of growth hormone on therapy resistance in cancer. Cancer Drug Resist. 2019;2:827–46.

    PubMed  PubMed Central  Google Scholar 

  123. (2016) Correction for Chesnokova et al., Growth hormone is permissive for neoplastic colon growth, Proc Natl Acad Sci U S A 113, E5251.

  124. Chesnokova V, Zonis S, Zhou C, Recouvreux MV, Ben-Shlomo A, Araki T, et al. Growth hormone is permissive for neoplastic colon growth. Proc Natl Acad Sci U S A. 2016;113:E3250–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Dhahbi J, Li X, Tran T, Masternak MM, Bartke A. Circulating blood leukocyte gene expression profiles: effects of the Ames dwarf mutation on pathways related to immunity and inflammation. Exp Gerontol. 2007;42:772–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet. 1993;4:227–32.

    Article  CAS  PubMed  Google Scholar 

  127. Gaylinn BD, Dealmeida VI, Lyons CE Jr, Wu KC, Mayo KE, Thorner MO. The mutant growth hormone-releasing hormone (GHRH) receptor of the little mouse does not bind GHRH. Endocrinology. 1999;140:5066–74.

    Article  CAS  PubMed  Google Scholar 

  128. Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG. Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature. 1993;364:208–13.

    Article  CAS  PubMed  Google Scholar 

  129. Lehman DM, Hale DE, Cody JT, Harrison JM, Leach RJ. Molecular, morphometric and functional analyses demonstrate that the growth hormone deficient little mouse is not hypomyelinated. Brain Res Dev Brain Res. 1999;116:191–9.

    Article  CAS  PubMed  Google Scholar 

  130. Donahue LR, Beamer WG. Growth hormone deficiency in 'little' mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, −1 or −4. J Endocrinol. 1993;136:91–104.

    Article  CAS  PubMed  Google Scholar 

  131. Mohan S, Richman C, Guo R, Amaar Y, Donahue LR, Wergedal J, et al. Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms. Endocrinology. 2003;144:929–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Christensen E, Wilson DB. Fine structure of somatotrophs and mammotrophs in the pituitary pars distalis of the little (lit) mutant mouse. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;37:89–96.

    Article  CAS  PubMed  Google Scholar 

  133. Kasukawa Y, Baylink DJ, Guo R, Mohan S. Evidence that sensitivity to growth hormone (GH) is growth period and tissue type dependent: studies in GH-deficient lit/lit mice. Endocrinology. 2003;144:3950–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wong JH, Dukes J, Levy RE, Sos B, Mason SE, Fong TS, et al. Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns. J Clin Invest. 2008;118:2969–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Fleenor D, Oden J, Kelly PA, Mohan S, Alliouachene S, Pende M, et al. Roles of the lactogens and somatogens in perinatal and postnatal metabolism and growth: studies of a novel mouse model combining lactogen resistance and growth hormone deficiency. Endocrinology. 2005;146:103–12.

    Article  CAS  PubMed  Google Scholar 

  136. del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA, et al. Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes. 2007;56:1638–46.

    Article  PubMed  CAS  Google Scholar 

  137. Foster MP, Jensen ER, Montecino-Rodriguez E, Leathers H, Horseman N, Dorshkind K. Humoral and cell-mediated immunity in mice with genetic deficiencies of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormone. Clin Immunol. 2000;96:140–9.

    Article  CAS  PubMed  Google Scholar 

  138. Amador-Noguez D, Yagi K, Venable S, Darlington G. Gene expression profile of long-lived Ames dwarf mice and little mice. Aging Cell. 2004;3:423–41.

    Article  CAS  PubMed  Google Scholar 

  139. Amador-Noguez D, Dean A, Huang W, Setchell K, Moore D, Darlington G. Alterations in xenobiotic metabolism in the long-lived little mice. Aging Cell. 2007;6:453–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yang XF, Beamer WG, Huynh H, Pollak M. Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation. Cancer Res. 1996;56:1509–11.

    CAS  PubMed  Google Scholar 

  141. Takahara K, Tearle H, Ghaffari M, Gleave ME, Pollak M, Cox ME. Human prostate cancer xenografts in lit/lit mice exhibit reduced growth and androgen-independent progression. Prostate. 2011;71:525–37.

    Article  CAS  PubMed  Google Scholar 

  142. Deitel K, Dantzer D, Ferguson P, Pollak M, Beamer W, Andrulis I, et al. Reduced growth of human sarcoma xenografts in hosts homozygous for the lit mutation. J Surg Oncol. 2002;81:75–9.

    Article  CAS  PubMed  Google Scholar 

  143. Alba M, Fintini D, Bowers CY, Parlow AF, Salvatori R. Effects of long-term treatment with growth hormone-releasing peptide-2 in the GHRH knockout mouse. Am J Physiol Endocrinol Metab. 2005;289:E762–7.

    Article  CAS  PubMed  Google Scholar 

  144. Alonso JR, Sanchez F, Arevalo R, Carretero J, Aijon J, Vazquez R. CaBP D-28k and NADPH-diaphorase coexistence in the magnocellular neurosecretory nuclei. Neuroreport. 1992;3:249–52.

    Article  CAS  PubMed  Google Scholar 

  145. Matzkin ME, Miquet JG, Fang Y, Hill CM, Turyn D, Calandra RS, et al. Alterations in oxidative, inflammatory and apoptotic events in short-lived and long-lived mice testes. Aging (Albany NY). 2016;8:95–110.

    Article  CAS  Google Scholar 

  146. Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, et al. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife. 2013;2:e01098.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Recinella L, Shohreh R, Salvatori R, Orlando G, Vacca M, Brunetti L. Effects of isolated GH deficiency on adipose tissue, feeding and adipokines in mice. Growth Hormon IGF Res. 2013;23:237–42.

    Article  CAS  Google Scholar 

  148. Leone S, Chiavaroli A, Shohreh R, Ferrante C, Ricciuti A, Manippa F, et al. Increased locomotor and thermogenic activity in mice with targeted ablation of the GHRH gene. Growth Hormon IGF Res. 2015;25:80–4.

    Article  CAS  Google Scholar 

  149. Fintini D, Alba M, Schally AV, Bowers CY, Parlow AF, Salvatori R. Effects of combined long-term treatment with a growth hormone-releasing hormone analogue and a growth hormone secretagogue in the growth hormone-releasing hormone knock out mouse. Neuroendocrinology. 2005;82:198–207.

    Article  CAS  PubMed  Google Scholar 

  150. Bodart G, Farhat K, Renard-Charlet C, Becker G, Plenevaux A, Salvatori R, et al. The severe deficiency of the Somatotrope GH-releasing hormone/growth hormone/insulin-like growth factor 1 Axis of Ghrh(−/−) mice is associated with an important splenic atrophy and relative B Lymphopenia. Front Endocrinol (Lausanne). 2018;9:296.

    Article  Google Scholar 

  151. Farhat K, Bodart G, Charlet-Renard C, Desmet CJ, Moutschen M, Beguin Y, et al. Growth hormone (GH) deficient mice with GHRH gene ablation are severely deficient in vaccine and immune responses against Streptococcus pneumoniae. Front Immunol. 2018;9:2175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Shohreh R, Pardo CA, Guaraldi F, Schally AV, Salvatori R. GH, but not GHRH, plays a role in the development of experimental autoimmune encephalomyelitis. Endocrinology. 2011;152:3803–10.

    Article  CAS  PubMed  Google Scholar 

  153. Leone S, Shohreh R, Manippa F, Recinella L, Ferrante C, Orlando G, et al. Behavioural phenotyping of male growth hormone-releasing hormone (GHRH) knockout mice. Growth Hormon IGF Res. 2014;24:192–7.

    Article  CAS  Google Scholar 

  154. Leone S, Recinella L, Chiavaroli A, Ferrante C, Orlando G, Vacca M, et al. Behavioural phenotyping, learning and memory in young and aged growth hormone-releasing hormone-knockout mice. Endocr Connect. 2018;7:924–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Recinella L, Leone S, Ferrante C, Chiavaroli A, Shohreh R, Di Nisio C, et al. Effects of growth hormone-releasing hormone gene targeted ablation on ghrelin-induced feeding. Growth Hormon IGF Res. 2017;37:40–6.

    Article  CAS  Google Scholar 

  156. Jensen, E. A., Young, J. A., Jackson, Z., Busken, J., List, E. O., Carroll, R. K., Kopchick, J. J., Murphy, E. R., and Berryman, D. E. (2020) Growth hormone deficiency and excess Alter the gut microbiome in adult male mice, Endocrinology 161.

Download references

Author information

Authors and Affiliations

  1. The Edison Biotechnology Institute, Ohio University, 172 Water Tower Drive, Athens, OH, 45701, USA

    Edward O. List, Reetobrata Basu, Silvana Duran-Ortiz, Jackson Krejsa & Elizabeth A. Jensen

  2. The Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA

    Edward O. List & Elizabeth A. Jensen

Authors
  1. Edward O. List
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reetobrata Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvana Duran-Ortiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jackson Krejsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth A. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EOL, RB, SD, JK and EAJ wrote and edited this manuscript.

Corresponding author

Correspondence to Edward O. List.

Ethics declarations

Conflicts of interest/competing interests

The authors have no conflicts of interest.

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

List, E.O., Basu, R., Duran-Ortiz, S. et al. Mouse models of growth hormone deficiency. Rev Endocr Metab Disord 22, 3–16 (2021). https://doi.org/10.1007/s11154-020-09601-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-020-09601-5

Keywords

Search

Navigation