19Analysis of TSC2-deficient hearts revealed the importance of autophagy in not only the quality but also the quantity control of mitochondria

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Purpose: Mammalian target of rapamycin complex 1 (mTORC1) is extremely important for cell growth and proliferation by activating protein synthesis. In addition, it also regulates protein degradation. There are two protein degradation systems in mammalian cells, namely autophagy and ubiquitin/proteasome systems. mTORC1 suppresses autophagic activity. We have previously reported that autophagy has a crucial role in maintaining cardiac structure and function in the heart. Tuberous sclerosis complex 1 (TSC1) and 2 heterodimer can inactivate ras homologue enriched in brain (Rheb) by the conversion of Rheb-GTP to Rheb-GDP in intracellular signalling pathway towards mTORC1, resulting in the inhibition of mTORC1 activity. It has been reported that ablation of Mtor in the adult mouse myocardium causes fatal and dilated cardiomyopathy. However, the role of mTORC1 in the regulation of autophagy is unclear. To investigate the role of mTORC1 under the condition of physiological inhibition in the heart, we generated cardiac-specific Rheb-deficient mice. Our study showed that Rheb is essential for mTORC1 signalling and normal cardiac development in the period of hypertrophy after proliferation. The aim of this study is to investigate the role of mTORC1 under the condition of physiological stimulation in the heart.

Results: We generated cardiac-specific TSC2-deficient mice. The TSC2-deficient mice died earlier than wild type mice, and the median life span was approximately 10 months. Echocardiographic parameters of the mice at 16 weeks of age showed LV chamber dilatation and LV contractile dysfunction. Physiological, histological and RT-qPCR analyses indicated cardiac hypertrophy, but not fibrosis. Western blotting analysis showed that the phosphorylation of S6 and 4EBP in the downstream of mTORC1 was upregulated in the heart and that autophagic activity was reduced. Ultrastructural analysis of the heart revealed disorganized, small and increased number of mitochondria, although mitochondrial respiratory functions or the content of ATP in the heart was not impaired.

Conclusion: These results suggest that continuous constitutive autophagy plays a crucial role in not only the quality but the quantity control of mitochondria to maintain cardiac structure and function.

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