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The role of mTOR complex 1 in skeletal muscle

Romanino, Klaas Emilio Antonius Anna. The role of mTOR complex 1 in skeletal muscle. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10185

Abstract

An important factor in energy and nutrient pathways is the mammalian target of rapamycin complex 1 (mTORC1). The multiprotein complex, with the central component mTOR, regulates cell growth and survival. Mice with muscle-specific inactivation of mTORC1 die after 4-6 months of respiratory failure caused by a progressive myopathy. Next to structural changes, like fiber atrophy, the deficiency of mTORC1 in muscle also causes metabolic alterations. Muscles of mTORC1-deficient mice show a decrease in oxidative capacity and fatty acid metabolism, caused by a reduced transcription of several mitochondrial genes. This is due to a reduced transcription of the master regulator of mitochondrial biogenesis, PGC-1α. Interestingly, transgenic or pharmacological increase of PGC-1α levels restores mitochondrial function in mice with ablated mTORC1 activity, but does not prevent the myopathy.
Additional metabolic changes in mTORC1-deficient muscle include glucose metabolism. Mice with inactivated mTORC1 in muscle show accumulations of glycogen, accompanied by a significant reduction of glucose uptake and glycolysis. The glycogen content is regulated through the activation of PKB/Akt, independently of PGC-1α. The reduction of glucose metabolism, in turn, correlates with an upregulation of the class II HDACs.
Besides inefficient nutrient uptake, mice lacking muscle mTORC1 increase their energy expenditure, which might be due to an upregulation of UCPs. Together, these metabolic changes lead to a protection against diet-induced obesity and hepatic steatosis. Thus, the mTORC1 is a central hub of metabolic pathways in skeletal muscle affecting systemic energy homeostasis.
Advisors:Rüegg, Markus A.
Committee Members:Handschin, Christoph
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
Item Type:Thesis
Thesis no:10185
Bibsysno:Link to catalogue
Number of Pages:77 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:28 Nov 2012 15:42

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