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Article

Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice

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Pages 1966-1975 | Received 28 Jan 2014, Accepted 07 Mar 2014, Published online: 20 Mar 2023
 

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.

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Articles of Significant Interest Selected from This Issue by the Editors

ACKNOWLEDGMENTS

We are grateful to Dario Alessi at the University of Dundee, Dundee, United Kingdom, for providing the Pdk1 floxed mice; Mark A. Magnuson at Vanderbilt University School of Medicine for providing the Rictor floxed mice; and Xiao Yang at Beijing Institute of Biotechnology, Beijing, China, for providing the αMHC-Cre mice.

This work was supported by the National Key Basic Research Program of China (2011CB943904, 2012CB966600, and 2006CB943503), the National Natural Science Foundation of China (31071282, 91019002, 31130037, 81100430, and 81170201), and Jiangsu Province Science and Technology Support Program (BE2009620 and BL2012015) with grants to Zhongzhou Yang, Xia Zhao, Yali Hu, and Xinli Li.

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