Bentzinger, Conrad Florian. Function of mTOR complex 1 and 2 in skeletal muscle. 2009, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_8589
To circumvent the early embryonic lethality of mice deficient for raptor (i.e. mTORC1) or rictor (i.e. mTORC2), we generated mice with floxed raptor or rictor alleles. Here we describe the phenotype of mice that lack functional mTORC1, mTORC2, or both complexes, specifically in skeletal muscle. We find that deletion of rictor does not cause an overt muscle phenotype. In contrast, raptor-deficient muscles manifest signs of atrophy and become progressively dystrophic. These muscles also display fundamental metabolic changes which involve impaired mitochondrial function. Furthermore, muscles display properties of fast-twitch, glycolytic skeletal muscle, but exhibit structural features and contraction properties indicative of slow-twitch, oxidative muscle fibers. These changes are either due to impaired activation of direct downstream substrates of mTORC1 or due to loss of negative feedback regulation of upstream components of the signaling pathway. Interestingly, this increased upstream signaling causes sustained hyperactivation of PKB/AKT, which is independent of mTORC2 kinase activity. Taken together, we provide unprecedented evidence for a crucial role of mTORC1 in the regulation of fundamental aspects of metabolism in a specific tissue. Furthermore we show that in the absence of negative feedback regulation from mTORC1 downstream components, mTORC2 is dispensable for PKB/AKT activation.
|Advisors:||Rüegg, Markus A.|
|Committee Members:||Zorzato, Francesco|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||66|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||08 Apr 2009 18:55|
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