Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mtor-mediated signaling and cardiac function

Wei Hua Shen, Zhuang Chen, Shu Shi, Hanying Chen, Wuqiang Zhu, Anne Penner, Guixue Bu, Wei Li, David Boyle, Michael Rubart-von der Lohe, Loren Field, Robert Abraham, Edward A. Liechty, Weinian Shou

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Abstract

Mammalian target of rapamycin (mTOR) is a key regulator for cell growth through modulating components of the translation machinery. Previously, numerous pharmacological studies using rapamycin suggested that mTOR has an important role in regulating cardiac hypertrophic growth. To further investigate this assumption, we have generated two lines of cardiac specific mTOR transgenic mice, kinase-dead (kd) mTOR and constitutively active (ca) mTOR, using α-myosin heavy chain promoter. α-Myosin heavy chain (αMHC)-mTORkd mice had a near complete inhibition of p70 S6k and 4E-BP1 phosphorylation, whereas αMHC-mTORca had a significant increase in p70 S6k and 4E-BP1 phosphorylation. Although the cardiac function of αMHC-mTORkd mice was significantly altered, the cardiac morphology of these transgenic mice was normal. The cardiac hypertrophic growth in response to physiological and pathological stimuli was not different in αMHC-mTORkd and αMHC-mTORca transgenic mice when compared with that of nontransgenic littermates. These findings suggest that the mTOR-mediated signaling pathway is not essential to cardiac hypertrophic growth but is involved in regulating cardiac function. Additional analysis of cardiac responses to fasting-refeeding or acute insulin administration indicated that αMHC-mTORkd mice had a largely impaired physiological response to nutrient energy supply and insulin stimulation.

Original languageEnglish
Pages (from-to)13842-13849
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number20
DOIs
StatePublished - May 16 2008

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Myosin Heavy Chains
Sirolimus
Phosphotransferases
Transgenic Mice
Phosphorylation
Growth
Insulin
Cardiac Myosins
Cell growth
Nutrients
Machinery
Fasting
Pharmacology
Food

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mtor-mediated signaling and cardiac function. / Shen, Wei Hua; Chen, Zhuang; Shi, Shu; Chen, Hanying; Zhu, Wuqiang; Penner, Anne; Bu, Guixue; Li, Wei; Boyle, David; Rubart-von der Lohe, Michael; Field, Loren; Abraham, Robert; Liechty, Edward A.; Shou, Weinian.

In: Journal of Biological Chemistry, Vol. 283, No. 20, 16.05.2008, p. 13842-13849.

Research output: Contribution to journalArticle

Shen, Wei Hua ; Chen, Zhuang ; Shi, Shu ; Chen, Hanying ; Zhu, Wuqiang ; Penner, Anne ; Bu, Guixue ; Li, Wei ; Boyle, David ; Rubart-von der Lohe, Michael ; Field, Loren ; Abraham, Robert ; Liechty, Edward A. ; Shou, Weinian. / Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mtor-mediated signaling and cardiac function. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 20. pp. 13842-13849.
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