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Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1

Mirko Völkers1, Haruhiro Toko, Shirin Doroudgar

  • 1San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA 92182, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 12, 2013
PubMed

Insights

Proline Rich AKT Substrate of 40 kDa (PRAS40) phosphorylation by AKT acts as a switch for cellular growth. This finding offers new therapeutic strategies for mitigating pathological cardiac hypertrophy.

Area of Science:

  • Cardiovascular Biology
  • Cellular Signaling
  • Molecular Medicine

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) regulates cellular growth but its control by PRAS40 in cardiac stress is unknown.
  • PRAS40 is an mTORC1 binding partner whose role in cardiac hypertrophy requires elucidation.

Purpose of the Study:

  • To investigate the role of PRAS40 in regulating mTORC1 activity and cardiac growth under physiological and pathological conditions.
  • To determine if AKT-mediated PRAS40 phosphorylation is essential for cardiac hypertrophy.

Main Methods:

  • In vitro studies using cardiomyocytes to assess PRAS40 regulation by AKT and its effect on mTORC1.
  • In vivo studies involving cardiomyocyte-specific overexpression of PRAS40 and a phosphorylation-deficient mutant in mouse models of cardiac stress.

Main Results:

  • PRAS40 is regulated by AKT in cardiomyocytes; AKT-driven phosphorylation inhibits PRAS40's suppressive effect on mTORC1.
  • PRAS40 overexpression in vitro and in vivo mitigates pathological cardiac hypertrophy and preserves function.
  • AKT-mediated PRAS40 phosphorylation is crucial for physiological cardiac hypertrophy, while its absence inhibits growth.

Conclusions:

  • PRAS40 phosphorylation by AKT functions as a molecular switch, enabling mTORC1 activation during physiological growth.
  • Targeting PRAS40 phosphorylation presents a novel therapeutic avenue for managing pathological myocardial hypertrophy.

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