title: 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.
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.
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Manabu
authors.initials: M
authors.lastname: Taneike
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Shigemiki
authors.initials: S
authors.lastname: Omiya
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Elham
authors.initials: E
authors.lastname: Zarrinpashneh
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Misaka
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Rika
authors.initials: R
authors.lastname: Kitazume-Taneike
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Austin
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takaoka
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.affiliation: Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D046912:Multiprotein Complexes / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014199:Trehalose / Q000494:pharmacology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D046912:Multiprotein Complexes; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D014199:Trehalose; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases