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J. Biol. Chem., Vol. 283, Issue 20, 13842-13849, May 16, 2008

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Cardiac Restricted Overexpression of Kinase-dead Mammalian Target of Rapamycin (mTOR) Mutant Impairs the mTOR-mediated Signaling and Cardiac Function^*

Wei-Hua Shen¹, Zhuang Chen¹, Shu Shi¹, Hanying Chen, Wuqiang Zhu, Anne Penner, Guixue Bu, Wei Li, David W. Boyle, Michael Rubart, Loren J. Field, Robert Abraham^¶, Edward A. Liechty², and Weinian Shou³

From the Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology and Neonatology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907, and the ^¶Department of Oncology Discovery, Wyeth, Pearl River, New York 10965

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 -myosin heavy chain promoter. -Myosin heavy chain (MHC)-mTOR^kd mice had a near complete inhibition of p70 S6k and 4E-BP1 phosphorylation, whereas MHC-mTOR^ca had a significant increase in p70 S6k and 4E-BP1 phosphorylation. Although the cardiac function of MHC-mTOR^kd 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 MHC-mTOR^kd and MHC-mTOR^ca 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 MHC-mTOR^kd mice had a largely impaired physiological response to nutrient energy supply and insulin stimulation.

Received for publication, February 25, 2008

^* This work was supported, in whole or in part, by National Institute of Health grants (to W. S. and L. J. F.). This work was also supported by the Riley Children's Foundation (to W. S., L. J. F., D. W. B., and E. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: eliecht{at}iupui.edu. ³ To whom correspondence may be addressed. E-mail: wshou{at}iupui.edu.