التفاصيل البيبلوغرافية
| العنوان: |
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. |
| المؤلفون: |
Manabu Taneike1, Kazuhiko Nishida1, Shigemiki Omiya1, Zarrinpashneh, Elham1, Tomofumi Misaka1, Rika Kitazume-Taneike1, Ruth Austin1, Minoru Takaoka1, Osamu Yamaguchi2, Gambello, Michael J.3, Shah, Ajay M.1, Kinya Otsu1 kinya.otsu@kcl.ac.uk |
| المصدر: |
PLoS ONE. 3/29/2016, Vol. 11 Issue 3, p1-18. 18p. |
| مصطلحات موضوعية: |
*MTOR inhibitors, *TUBERIN, *HEART diseases, *DOWNREGULATION, *CELL proliferation |
| مستخلص: |
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 amajor systemto 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 themitochondrial function wasmaintained. 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. [ABSTRACT FROM AUTHOR] |
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