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Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation.

Abstract：

:Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK-mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Hasumi Y,Baba M,Hasumi H,Huang Y,Lang M,Reindorf R,Oh HB,Sciarretta S,Nagashima K,Haines DC,Schneider MD,Adelstein RS,Schmidt LS,Sadoshima J,Marston Linehan W

doi

10.1093/hmg/ddu286

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

5706-19

issue

eissn

0964-6906

issn

1460-2083

pii

ddu286

journal_volume

pub_type

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Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation.