Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1

Mirko Völkers, Haruhiro Toko, Shirin Doroudgar, Shabana Din, Pearl Quijada, Anya Y. Joyo, Luis Ornelas, Eri Joyo, Donna J. Thuerauf, Mathias H. Konstandin, Natalie Gude, Christopher C. Glembotski, Mark A. Sussman

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40.

Original languageEnglish (US)
Pages (from-to)12661-12666
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number31
DOIs
StatePublished - Jul 30 2013
Externally publishedYes

ASJC Scopus subject areas

  • General

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