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Dissecting the roles of mTORC1 and mTORC2 in the mouse heart

Shende, Pankaj. Dissecting the roles of mTORC1 and mTORC2 in the mouse heart. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10383

Abstract

Mammalian target of rapamycin (mTOR) is an evolutionary conserved serine/threonine kinase that regulates cell growth and metabolism. mTOR occurs in cells in two complexes, termed mTORC1 and mTORC2. This thesis describes investigations into the in vivo functions of these two complexes in the mouse heart.
The first part of the thesis focuses on the characterization of the role of mTORC1 in the adult heart. To inactivate mTORC1 for analysis of its cardiac functions, we ablated the mTORC1-specific and essential component raptor selectively and conditionally from cardiomyocytes using cre-loxP recombination. The resulting knockout mice showed decreased cardiac function at 3 weeks after gene deletion, culminating in heart failure and death after 5 weeks. Furthermore, the mice were exposed to voluntary wheel running exercise to trigger physiological cardiac growth, or to pathological stress, which was induced by aortic banding. Increased mortality was observed after exercise. In response to aortic banding, the raptor knockout mice lacked the phase of adaptive hypertrophic growth that normally occurs and went directly into dilated cardiomyopathy. In addition, the raptor knockout mice changed their cardiac mitochondrial gene expression pattern and switched from fatty acids to glucose as their primary source of energy. The decrease in cardiac function was accompanied by increased apoptosis and autophagy along with distorted mitochondrial structure. In conclusion, our findings establish mTORC1 as important regulator of cardiac homeostasis.
The second part of the thesis describes the in vivo function of mTORC2 in the heart. We used a similar approach as for mTORC1 to delete the mTORC2-specific component rictor selectively from cardiomyocytes. At baseline, during adulthood, rictor deletion had no effect on cardiac function. Cardiac geometry was normal in the cardiac rictor knockout mice despite the fact that downstream of mTORC2, phosphorylated and total Akt and PKC levels were significantly reduced. In contrast, conditions of pathological stress induced by aortic banding caused decreased cardiac function in the rictor knockout mice. The mice had a phenotype of eccentric hypertrophy with changed chamber dimensions. Increased fibrosis and apoptosis were accompanied by enhanced reexpression of fetal genes compared to wild-type mice. On the other hand, deletion of rictor during postnatal growth did not show any functional or geometrical changes of the heart. Overall, the data demonstrates that rictor/mTORC2 is important for cardiac function during the adaptation to pathological stress.
Advisors:Hall, Michael N.
Committee Members:Brink, Marijke and Handschin, Christoph
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
Item Type:Thesis
Thesis no:10383
Bibsysno:Link to catalogue
Number of Pages:119 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:53
Deposited On:24 Jun 2013 14:01

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