title: 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.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hasumi
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Lang
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Reindorf
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hyoung-bin
authors.initials: HB
authors.lastname: Oh
authors.affiliation: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101, USA, IRCCS Neuromed, Località Camerelle, 86077, Pozzilli (IS), Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: Image Analysis Laboratory.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Pathology/Histotechnology Laboratory.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Haines
authors.affiliation: British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Laboratory of Molecular Cardiology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Adelstein
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.affiliation: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, wml@nih.gov.
authors.forename: W
authors.initials: W
authors.lastname: Marston Linehan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004970:Estrone / Q000235:genetics*; D020868:Gene Silencing; D006333:Heart Failure / Q000209:etiology / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D063269:Mitochondrial Turnover; D046912:Multiprotein Complexes / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D046912:Multiprotein Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D004970:Estrone; D000255:Adenosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus