title: Phosphoinositide-dependent kinase 1 and mTORC2 synergistically maintain postnatal heart growth and heart function in mice.
abstract: The protein kinase Akt plays a critical role in heart function and is activated by phosphorylation of threonine 308 (T308) and serine 473 (S473). While phosphoinositide-dependent kinase 1 (PDK1) is responsible for Akt T308 phosphorylation, the identities of the kinases for Akt S473 phosphorylation in the heart remain controversial. Here, we disrupted mTOR complex 2 (mTORC2) through deletion of Rictor in the heart and found normal heart growth and function. Rictor deletion caused significant reduction of Akt S473 phosphorylation but enhanced Akt T308 phosphorylation, suggesting that a high level of Akt T308 phosphorylation maintains Akt activity and heart function. Deletion of Pdk1 in the heart caused significantly enhanced Akt S473 phosphorylation that was suppressed by removal of Rictor, leading to worsened dilated cardiomyopathy (DCM) and accelerated heart failure in Pdk1-deficient mice. In addition, we found that increasing Akt S473 phosphorylation through deletion of Pten or chemical inhibition of PTEN reversed DCM and heart failure in Pdk1-deficient mice. Investigation of heart samples from human DCM patients revealed changes similar to those in the mouse models. These results demonstrated that PDK1 and mTORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.
authors.affiliation: Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Lu
authors.forename: Junwei
authors.initials: J
authors.lastname: Nie
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Hu
authors.forename: Wen
authors.initials: W
authors.lastname: Luo
authors.forename: Xiangqi
authors.initials: X
authors.lastname: Wu
authors.forename: Hailang
authors.initials: H
authors.lastname: Liu
authors.forename: Qiuting
authors.initials: Q
authors.lastname: Feng
authors.forename: Zai
authors.initials: Z
authors.lastname: Chang
authors.forename: Yaoqiu
authors.initials: Y
authors.lastname: Liu
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Cao
authors.forename: Haixiang
authors.initials: H
authors.lastname: Sun
authors.forename: Xinli
authors.initials: X
authors.lastname: Li
authors.forename: Yali
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D006321:Heart / Q000254:growth & development* / Q000502:physiology; D006333:Heart Failure / Q000235:genetics; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D064413:3-Phosphoinositide-Dependent Protein Kinases; D000076225:Mechanistic Target of Rapamycin Complex 2; C578564:Pdpk1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse