title: Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice.
abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor(flox/flox) mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function.
authors.affiliation: Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Tizhong
authors.initials: T
authors.lastname: Shan
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Liang
authors.affiliation: Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Changyan
authors.initials: C
authors.lastname: Deng
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA. Electronic address: skuang@purdue.edu.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
mesh_terms: D000818:Animals; D006321:Heart / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Cardiomyocyte; Heart failure; mTOR