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J Mol Cell Cardiol. 2016 Aug;97:213-25. doi: 10.1016/j.yjmcc.2016.04.011. Epub 2016 Apr 28.

mTOR inactivation in myocardium from infant mice rapidly leads to dilated cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis.

Author information

1
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.
2
CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.
3
CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France.
4
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.
5
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.
6
INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de medicine, Rockefeller et Charles Merieux Lyon-Sud, Lyon 69003, France.
7
INRA, UMR 1019, UNH, CRNH, F-63000, Auvergne, Clermont-Ferrand, France.
8
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.

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.

KEYWORDS:

Cardiomyocyte apoptosis; Heart postnatal development; Myocardial metabolism; Signal transduction; Translation; mTOR

PMID:
27133769
DOI:
10.1016/j.yjmcc.2016.04.011
[Indexed for MEDLINE]

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