Akt is serine/threonine protein kinase associated with various cellular processes and 3 different isoforms exist. This work describes the reproductive phenotype of Akt1−/− and Akt2−/− in male mice. The seminiferous tubule diameter in Akt1−/− testes was less than wild-type or Akt2−/− testes. The expression of phospho-phosphatase and tensin homologue deleted on chromosome 10 (p-PTEN) and phospho-glycogen synthase kinase 3β (GSK-3β) was elevated in Akt1−/− testes. Alterations in expression and localization to the plasma membrane of several facilitative glucose transporters (Slc2a8, 9a and 9b) were detected in these knockout compared to wild-type mice. Apoptotic sperm were more prevalent in both null mice compared to wild-type mice, whereas sperm concentration and motility were significantly lower in the null sperm. Finally, Akt2−/− sperm had a markedly decreased fertilization rate by in vitro fertilization (IVF) and resulting embryos displayed increased fragmentation and poor growth. These results suggest that altered SLC2A expression and increased PTEN and GSK3β activity may be responsible for the decreased spermatogenesis, sperm maturation, and fertilization in the Akt1−/− and Akt2−/− male mice.
KandelESHayN. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999;253(1):210–229.
2.
DattaSRBrunetAGreenbergME. Cellular survival: a play in three Akts. Genes Dev. 1999;13(22):2905–2927.
3.
BrazilDPYangZZHemmingsBA. Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci. 2004;29(5):233–242.
4.
AltomareDALyonsGEMitsuuchiYChengJQTestaJR. Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin. Oncogene. 1998;16(18):2407–2411.
5.
YangZZTschoppOHemmings-MieszczakMProtein kinase B alpha/Akt1 regulates placental development and fetal growth. J Biol Chem. 2003;278(34):32124–32131.
6.
ChenWSXuPZGottlobKGrowth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 2001;15(17):2203–2208.
7.
ChoHThorvaldsenJLChuQFengFBirnbaumMJ. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem. 2001;276(42):38349–38352.
8.
AltomareDAGuoKChengJQSonodaGWalshKTestaJR. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene. 1995;11(6):1055–1060.
9.
GarofaloRSOrenaSJ. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003;112(2):197–208.
10.
BrodbeckDCronPHemmingsBA. A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem. 1999;274(2):9133–9136.
11.
NakataniKSakaueHThompsonDAWeigelRJRothRA. Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochem Biophys Res Commun. 1999;257(3):906–910.
12.
TschoppOYangZZBrodbeckDEssential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development. 2005;132(13):2943–2954.
13.
PengXDXuPZChenMLDwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 2003;17(11):1352–1365.
14.
YangZZTschoppODi-PoïNDosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Mol Cell Biol. 2005;25(23):10407–10418.
15.
DummlerBTschoppOHynxDYangZZDirnhoferSHemmingsBA. Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol. 2006;26(21):8042–8051.
16.
BaeSSChoHMuJBirnbaumMJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem. 2003;278(49):49530–49536.
17.
KimSTMoleyKH. The expression of GLUT8, GLUT9a, and GLUT9b in the mouse testis and sperm. Reprod Sci. 2007;14(5):445–455.
18.
KimSTMoleyK. Paternal effect on embryo quality in diabetic mice is related to poor sperm quality and associated with decreased GLUT expression. Reproduction. 2008;136(3):313–322.
19.
JoostHGBellGIBestJDNomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab. 2002;282(4):E974–E976.
20.
KeembiyehettyCAugustinRCarayannopoulosMOMouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes. Mol Endocrinol. 2006;20(3):686–697.
21.
CarayannopoulosMOChiMMCuiYGLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. Proc Natl Acad Sci U S A. 2000;97(13):7313–7318.
22.
AugustinRRileyJMoleyKH. GLUT8 contains a [DE]XXXL[LI] sorting motif and localizes to a late endosomal/lysosomal compartment. Traffic.2005;6(12):1196–1212.
Santos-AhmedJBrownCSmithSDAkt1 protects against germ cell apoptosis in the postnatal mouse testis following lactational exposure to 6-N-propylthiouracil. Reprod Toxicol. 2011;31(1):17–25.
27.
PintoABCarayannopoulosMOHoehnADowdLMoleyKH. Glucose transporter 8 expression and translocation are critical for murine blastocyst survival. Biol Reprod. 2002;66(6):1729–1733.
28.
GorovitsNCuiLBusikJVRanallettaMHauguel de-MouzonSCharronMJ. Regulation of hepatic GLUT8 expression in normal and diabetic models. Endocrinology. 2003;144(5):1703–1711.
29.
HanXXHandbergAPetersenLNPlougTGalboH. Stability of GLUT-1 and GLUT-4 expression in perfused rat muscle stimulated by insulin and exercise. J Appl Physiol. 1995;78(1):46–52.
30.
FreemanJEWolfCR. Evidence against a role for serine 129 in determining murine cytochrome P450 Cyp2e-1 protein levels. Biochemistry. 1994;33(47):13963–13966.
31.
CantleyLCNeelBG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999;96(8):4240–4245.
32.
MyersMPStolarovJPEngC P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997;94(17):9052–9057.
33.
WanXHelmanLJ. Levels of PTEN protein modulate Akt phosphorylation on serine 473, but not on threonine 308, in IGF-II-overexpressing rhabdomyosarcomas cells. Oncogene. 2003;22(50):8205–8211.
34.
WuXSenechalKNeshatMSWhangYESawyersCL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1998;95(26):15587–15591.
35.
VazquezFRamaswamySNakamuraNSellersWR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol. 2000;20(14):5010–5018.
36.
TorresJPulidoR. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem. 2001;276(2):993–998.
37.
WelshGIWilsonCProudCG. GSK3: a SHAGGY frog story. Trends Cell Biol. 1996;6(7):274–279.
38.
SrivastavaAKPandeySK. Potential mechanism(s) involved in the regulation of glycogen synthesis by insulin. Mol Cell Biochem. 1998;182(1-2):135–141.
39.
CrossDAAlessiDRCohenPAndjelkovichMHemmingsBA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378(6559):785–789.
40.
ZhengXXieLQinJShenHChenZJinY. Effects of wortmannin on phosphorylation of PDK1, GSK3-beta, PTEN and expression of Skp2 mRNA after ischemia/reperfusion injury in the mouse kidney. Int Urol Nephrol. 2008;40(1):185–192.
41.
FinkielszteinAKellyGM. Altering PI3K-Akt signalling in zebrafish embryos affects PTEN phosphorylation and gastrulation. Biol Cell. 2009;101(11):661–678.
42.
KimNHJeonSLeeHJLeeAY. Impaired PI3K/Akt activation-mediated NF-kappaB inactivation under elevated TNF-alpha is more vulnerable to apoptosis in vitiliginous keratinocytes. J Invest Dermatol. 2007;127(11):2612–2617.
43.
MulhollandDJDedharSWuHNelsonCC. PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. Oncogene. 2006;25(3):329–337.
44.
HoskinsDDMunstermanDHallML. The control of bovine sperm glycolysis during epididymal transit. Biol Reprod. 1975;12(5):566–572.
45.
UrnerFSakkasD. A possible role for the pentose phosphate pathway of spermatozoa in gamete fusion in the mouse. Biol Reprod. 1999;60(3):733–739.
46.
JelodarGKhaksarZPourahmadiM. Endocrine profile and testicular histomorphometry in adult rat offspring of diabetic mothers. J Physiol Sci. 2009;59(5):377–382.
47.
MurrayFTCameronDFOrthJM. Gonadal dysfunction in the spontaneously diabetic BB rat. Metabolism. 1983;32(7 suppl 1):141–147.
48.
ScaranoWRMessiasAGOlivaSUKlinefelterGRKempinasWG. Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats. Int J Androl. 2006;29(4):482–488.
49.
SeethalakshmiLMenonMDiamondD. The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat. J Urol. 1987;138(1):190–194.
50.
BenerAAl-AnsariAAZirieMAl-HamaqAO. Is male fertility associated with type 2 diabetes mellitus?Int Urol Nephrol. 2009;41(4):777–784.
51.
MallidisCAgbajeIMcClureNKlieschS. [The influence of diabetes mellitus on male reproductive function: a poorly investigated aspect of male infertility]. Urologe A. 2011;50(1):33–37.
52.
BaccettiBLa MarcaAPiomboniPInsulin-dependent diabetes in men is associated with hypothalamo-pituitary derangement and with impairment in semen quality. Hum Reprod. 2002;17(10):2673–2677.
53.
ShrivastavPSwannJJeremyJYThompsonCShawRWDandonaP. Sperm function and structure and seminal plasma prostanoid concentrations in men with IDDM. Diabetes Care. 1989;12(10):742–744.
