The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload

Masataka Ikeda, Tomomi Ide, Takeo Fujino, Yuka Matsuo, Shinobu Arai, Keita Saku, Takamori Kakino, Yasuhiro Oga, Akiko Nishizaki, Kenji Sunagawa

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart.

Original languageEnglish
Article number15881
JournalScientific reports
Volume5
DOIs
Publication statusPublished - Oct 30 2015

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Sirolimus
Hypertrophy
Blood Pressure
Cardiomegaly
Cardiac Output
Atrophy
Intercellular Signaling Peptides and Proteins
Hemodynamics
Pressure
Membranes

All Science Journal Classification (ASJC) codes

  • General

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The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload. / Ikeda, Masataka; Ide, Tomomi; Fujino, Takeo; Matsuo, Yuka; Arai, Shinobu; Saku, Keita; Kakino, Takamori; Oga, Yasuhiro; Nishizaki, Akiko; Sunagawa, Kenji.

In: Scientific reports, Vol. 5, 15881, 30.10.2015.

Research output: Contribution to journalArticle

Ikeda, M, Ide, T, Fujino, T, Matsuo, Y, Arai, S, Saku, K, Kakino, T, Oga, Y, Nishizaki, A & Sunagawa, K 2015, 'The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload', Scientific reports, vol. 5, 15881. https://doi.org/10.1038/srep15881
Ikeda, Masataka ; Ide, Tomomi ; Fujino, Takeo ; Matsuo, Yuka ; Arai, Shinobu ; Saku, Keita ; Kakino, Takamori ; Oga, Yasuhiro ; Nishizaki, Akiko ; Sunagawa, Kenji. / The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload. In: Scientific reports. 2015 ; Vol. 5.
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