ArticlePloS one2016
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.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice.Epigenetics · 2025Article
- MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis.Nature communications · 2025Article
- Review
- A neuroprotective dose of trehalose is harmless to metabolic organs: comprehensive histopathological analysis of liver, pancreas, and kidney.Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences · 2023Article
- Article
- New Insights into the Regulation of mTOR Signaling via CaInternational journal of molecular sciences · 2023Review
- Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia.Heliyon · 2022Article
- ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice.The Journal of clinical investigation · 2022Article
- The complex network of mTOR signalling in the heart.Cardiovascular research · 2022Review
- Autophagy in striated muscle diseases.Frontiers in cardiovascular medicine · 2022Review
- Autophagy in major human diseases.The EMBO journal · 2021Review
- Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.Aging cell · 2021Article
- Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy.Journal of molecular and cellular cardiology · 2021Article
- Review
- Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state.Genetics and molecular biology · 2021Article
- The paradox of autophagy in Tuberous Sclerosis Complex.Genetics and molecular biology · 2021Article
- PKG1α Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy.Circulation research · 2020Article
- Review
- Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms.Frontiers in physiology · 2020Review
- Podocyte-specific deletion of tubular sclerosis complex 2 promotes focal segmental glomerulosclerosis and progressive renal failure.PloS one · 2020Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
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.
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