PMID- 27133769
OWN - NLM
STAT- MEDLINE
DCOM- 20170531
LR  - 20211204
IS  - 1095-8584 (Electronic)
IS  - 0022-2828 (Linking)
VI  - 97
DP  - 2016 Aug
TI  - mTOR inactivation in myocardium from infant mice rapidly leads to dilated 
      cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis.
PG  - 213-25
LID - S0022-2828(16)30077-3 [pii]
LID - 10.1016/j.yjmcc.2016.04.011 [doi]
AB  - Mechanistic target of rapamycin (mTOR) is a central regulator of cell growth, 
      proliferation, survival and metabolism, as part of mTOR complex 1 (mTORC1) and 
      mTORC2. While partial inhibition of mTORC1 using rapamycin was shown to be 
      cardioprotective, genetic studies in mouse models revealed that mTOR is essential 
      for embryonic heart development and cardiac function in adults. However, the 
      physiological role of mTOR during postnatal cardiac maturation is not fully 
      elucidated. We have therefore generated a mouse model in which cardiac mTOR was 
      inactivated at an early postnatal stage. Mutant mTORcmKO mice rapidly developed a 
      dilated cardiomyopathy associated with cardiomyocyte growth defects, apoptosis 
      and fibrosis, and died during their third week. Here, we show that reduced 
      cardiomyocyte growth results from impaired protein translation efficiency through 
      both 4E-BP1-dependent and -independent mechanisms. In addition, infant mTORcmKO 
      hearts displayed markedly increased apoptosis linked to stretch-induced ANKRD1 
      (Ankyrin repeat-domain containing protein 1) up-regulation, JNK kinase activation 
      and p53 accumulation. Pharmacological inhibition of p53 with pifithrin-alpha 
      attenuated caspase-3 activation. Cardiomyocyte death did not result from 
      activation of the MST1/Hippo pro-apoptotic pathway as reported in adult 
      rictor/mTORC2 KO hearts. As well, mTORcmKO hearts showed a strong downregulation 
      of myoglobin content, thereby leading to a hypoxic environment. Nevertheless, 
      they lacked a HIF1alpha-mediated adaptive response, as mTOR is required for 
      hypoxia-induced HIF-1alpha activation. Altogether, our results demonstrate that mTOR 
      is critically required for cardiomyocyte growth, viability and oxygen supply in 
      early postnatal myocardium and provide insight into the molecular mechanisms 
      involved in apoptosis of mTOR-depleted cardiomyocytes.
CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
FAU - Mazelin, Laetitia
AU  - Mazelin L
AD  - Universite Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut 
      NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de 
      Biologie Moleculaire de la Cellule, ENS Lyon, 46 Allee d'Italie, 69364 Lyon cedex 
      07, France. Electronic address: laetitia.mazelin@ens-lyon.fr.
FAU - Panthu, Baptiste
AU  - Panthu B
AD  - CIRI, International Center for Infectiology Research, Universite de Lyon, Lyon, 
      France.
FAU - Nicot, Anne-Sophie
AU  - Nicot AS
AD  - CNRS UMR 5239, Laboratoire de Biologie Moleculaire de la Cellule, ENS Lyon, 46 
      Allee d'Italie, 69364 Lyon cedex 07, France.
FAU - Belotti, Edwige
AU  - Belotti E
AD  - Universite Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut 
      NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de 
      Biologie Moleculaire de la Cellule, ENS Lyon, 46 Allee d'Italie, 69364 Lyon cedex 
      07, France.
FAU - Tintignac, Lionel
AU  - Tintignac L
AD  - Neuromuscular Research Center, Departments of Neurology and Biomedicine, 
      Pharmazentrum, Basel University Hospital, 4056 Basel, Switzerland; INRA, UMR866 
      Dynamique Musculaire et Metabolisme, Universite Montpellier 1, F 34060 
      Montpellier, France.
FAU - Teixeira, Geoffrey
AU  - Teixeira G
AD  - INSERM UMR-1060, Laboratoire CarMeN, Universite Lyon 1, Faculte de medicine, 
      Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
FAU - Zhang, Qing
AU  - Zhang Q
AD  - CNRS UMR 5239, Laboratoire de Biologie Moleculaire de la Cellule, ENS Lyon, 46 
      Allee d'Italie, 69364 Lyon cedex 07, France.
FAU - Risson, Valerie
AU  - Risson V
AD  - Universite Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut 
      NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de 
      Biologie Moleculaire de la Cellule, ENS Lyon, 46 Allee d'Italie, 69364 Lyon cedex 
      07, France.
FAU - Baas, Dominique
AU  - Baas D
AD  - Universite Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut 
      NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de 
      Biologie Moleculaire de la Cellule, ENS Lyon, 46 Allee d'Italie, 69364 Lyon cedex 
      07, France.
FAU - Delaune, Emilie
AU  - Delaune E
AD  - CNRS UMR 5239, Laboratoire de Biologie Moleculaire de la Cellule, ENS Lyon, 46 
      Allee d'Italie, 69364 Lyon cedex 07, France.
FAU - Derumeaux, Genevieve
AU  - Derumeaux G
AD  - INSERM UMR-1060, Laboratoire CarMeN, Universite Lyon 1, Faculte de medicine, 
      Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
FAU - Taillandier, Daniel
AU  - Taillandier D
AD  - INRA, UMR 1019, UNH, CRNH, F-63000, Auvergne, Clermont-Ferrand, France.
FAU - Ohlmann, Theophile
AU  - Ohlmann T
AD  - CIRI, International Center for Infectiology Research, Universite de Lyon, Lyon, 
      France.
FAU - Ovize, Michel
AU  - Ovize M
AD  - INSERM UMR-1060, Laboratoire CarMeN, Universite Lyon 1, Faculte de medicine, 
      Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
FAU - Gangloff, Yann-Gael
AU  - Gangloff YG
AD  - Universite Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut 
      NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de 
      Biologie Moleculaire de la Cellule, ENS Lyon, 46 Allee d'Italie, 69364 Lyon cedex 
      07, France.
FAU - Schaeffer, Laurent
AU  - Schaeffer L
AD  - Universite Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut 
      NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de 
      Biologie Moleculaire de la Cellule, ENS Lyon, 46 Allee d'Italie, 69364 Lyon cedex 
      07, France; Hospices Civils de Lyon, Service d'Anatomie et Cytologie 
      Pathologiques, Hopital Edouard Herriot, France.
LA  - eng
PT  - Journal Article
DEP - 20160428
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Ankrd1 protein, mouse)
RN  - 0 (Biomarkers)
RN  - 0 (Muscle Proteins)
RN  - 0 (Myoglobin)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/*genetics
MH  - Biomarkers
MH  - Biopsy
MH  - Cardiomyopathy, Dilated/*genetics/*metabolism/pathology/physiopathology
MH  - Cardiopulmonary Bypass
MH  - Disease Models, Animal
MH  - Echocardiography
MH  - Energy Metabolism/genetics
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - Heart Function Tests
MH  - JNK Mitogen-Activated Protein Kinases/*genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle Proteins/metabolism
MH  - Myoglobin/metabolism
MH  - Nuclear Proteins/metabolism
MH  - *Protein Biosynthesis
MH  - Proteolysis
MH  - Repressor Proteins/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tumor Suppressor Protein p53/*genetics/metabolism
OTO - NOTNLM
OT  - Cardiomyocyte apoptosis
OT  - Heart postnatal development
OT  - Myocardial metabolism
OT  - Signal transduction
OT  - Translation
OT  - mTOR
EDAT- 2016/05/03 06:00
MHDA- 2017/06/01 06:00
CRDT- 2016/05/03 06:00
PHST- 2015/10/20 00:00 [received]
PHST- 2016/04/05 00:00 [revised]
PHST- 2016/04/12 00:00 [accepted]
PHST- 2016/05/03 06:00 [entrez]
PHST- 2016/05/03 06:00 [pubmed]
PHST- 2017/06/01 06:00 [medline]
AID - S0022-2828(16)30077-3 [pii]
AID - 10.1016/j.yjmcc.2016.04.011 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2016 Aug;97:213-25. doi: 10.1016/j.yjmcc.2016.04.011. Epub 
      2016 Apr 28.