title: mTOR inactivation in myocardium from infant mice rapidly leads to dilated cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis.
abstract: 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-α 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 HIF1α-mediated adaptive response, as mTOR is required for hypoxia-induced HIF-1α 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.
authors.affiliation: Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France. Electronic address: laetitia.mazelin@ens-lyon.fr.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Mazelin
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Panthu
authors.affiliation: CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Nicot
authors.affiliation: Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Belotti
authors.affiliation: Neuromuscular Research Center, Departments of Neurology and Biomedicine, Pharmazentrum, Basel University Hospital, 4056 Basel, Switzerland; INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F 34060 Montpellier, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Tintignac
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Teixeira
authors.affiliation: CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Risson
authors.affiliation: Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baas
authors.affiliation: CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Delaune
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Derumeaux
authors.affiliation: INRA, UMR 1019, UNH, CRNH, F-63000, Auvergne, Clermont-Ferrand, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Taillandier
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.
authors.forename: Théophile
authors.initials: T
authors.lastname: Ohlmann
authors.affiliation: INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
authors.affiliation: Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Yann-Gaël
authors.initials: YG
authors.lastname: Gangloff
authors.affiliation: Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGene, F-69622 Villeurbanne, France; CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France; Hospices Civils de Lyon, Service d'Anatomie et Cytologie Pathologiques, Hôpital Édouard Herriot, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015415:Biomarkers; D001706:Biopsy; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002315:Cardiopulmonary Bypass; D004195:Disease Models, Animal; D004452:Echocardiography; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006334:Heart Function Tests; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D009211:Myoglobin / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C104844:Ankrd1 protein, mouse; D015415:Biomarkers; D009124:Muscle Proteins; D009211:Myoglobin; D009687:Nuclear Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cardiomyocyte apoptosis; Heart postnatal development; Myocardial metabolism; Signal transduction; Translation; mTOR