mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy.

• Type of Material: Article
• Authors: Manabu Taneike, King’s College London; Kazuhiko Nishida, King’s College London; Shigemiki Omiya, King’s College London; Elham Zarrinpashneh, King’s College London; Tomofumi Misaka, King’s College London; Rika Kitazume-Taneike, King’s College London; Ruth Austin, King’s College London; Minoru Takaoka, King’s College London; Osamu Yamaguchi, Osaka University; Michael Gambello, Emory University; Ajay M. Shah, King’s College London; Kinya Otsu, King’s College London
• Language: English
• Date: 2016
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Taneike et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0152628
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 3
• Start Page: e0152628
• End Page: e0152628
• Grant/Funding Information: This work was supported by Medical Research Council (MR/K019031/1), http://www.mrc.ac.uk/, KO; British Heart Foundation (CH/11/3/29051, RG/11/12/29052), https://www.bhf.org.uk/, KO.
• Keywords: Mouse models; Phosphorylation; Trehalose; Heart; Autophagic cell death; Cardiovascular physiology; Mitochondria; Protein synthesis
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts.