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The role of mTORC1 in muscle proteostasis

Kaiser, Marco. The role of mTORC1 in muscle proteostasis. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13247

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Abstract

Skeletal muscle is crucial for human daily life. It is essential for locomotion and breathing and it affects whole-body metabolism. Preservation of muscle mass is thus critical to maintain body function and health. Current views indicate that muscle mass is controlled by the tight balance between protein synthesis and protein degradation, called proteostasis. Perturbation of this balance by extrinsic factors, as for example seen in cachexia (i.e., muscle loss as a secondary consequence of e.g. cancer, AIDS, or cardiac and kidney disease) or in sarcopenia (i.e., loss of muscle mass and function as a consequence of aging), is a main cause of loss of life quality and increased mortality. Thus, a better molecular understanding of muscle proteostasis is of fundamental importance to develop possible treatment strategies to counteract the above diseases.
Two major regulators of muscle proteostasis are the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) and the forkhead box O (FoxO) transcription factors. While mTORC1 controls proteostasis by increasing translation and protein synthesis, FoxO regulates catabolic processes by increasing the expression of genes encoding for proteins involved in protein degradation. Thus, increased activation of FoxO causes muscle loss (atrophy), whereas activation of mTORC1 is associated with muscle gain (hypertrophy). However and in striking contrast to the expected outcome of muscle gain, sustained activation of mTORC1 in muscle by knockout of its upstream inhibitor TSC1 (TSCmKO mice) results in atrophy. This phenotype is observed despite the marked increase in protein synthesis. Hence, the mechanisms involved in muscle atrophy in TSCmKO mice remain unresolved.
The purpose of this thesis was to provide new insights on the role of mTORC1 in regulating muscle proteostasis. Particularly, to characterize the mechanism of this mTORC1-driven atrophy observed in TSCmKO mice. Furthermore, the aim was to investigate if sustained activation of mTORC1 increases overall protein degradation via the thymoma viral proto-oncogene (Akt)-FoxO-signaling or by distinct other catabolic pathways.
In this thesis, it was established that sustained activation of mTORC1 in muscles of TSCmKO mice leads to a significant increase of the ubiquitin-proteasome system (UPS). This was characterized by increased expression of ubiquitin-E3-ligases, increased ubiquitinylation, increased proteasomal biosynthesis and increased proteasome activity. The increase of the UPS was reversed by short-term treatment with the mTORC1-inhibitor rapamycin. Interestingly, the same increase of the UPS was observed upon acute muscle-specific deletion of Tsc1 for 3 weeks. Surprisingly, constitutive activation of Akt in muscle resulted in a similar induction of proteasomal biosynthesis and proteasome activity as observed in TSCmKO mice. Hence, this suggests a mechanism, which is independent of the activation of FoxO transcription factors. Finally, it was established that the increased UPS activity was accompanied by a concomitant increase of the transcription factor “nuclear factor, erythroid-derived 2,-like 1” (NFE2L1, hereafter called Nrf1).
In short, this thesis demonstrated that mTORC1 activation is a major driver of the ubiquitin-proteasome system in skeletal muscle and identified Nrf1, together with FoxO transcription factors, as a key mediator of this pathway. Both, mTORC1 signaling as well as the UPS are considered as potential treatment targets in a large variety of distinct muscle wasting diseases. Therefore, understanding the underlying regulatory mechanisms of how mTORC1 controls muscle mass is of fundamental importance to eventually develop new therapeutic agents that could slow-down the massive muscle wasting observed in cachexia and sarcopenia.
Advisors:Rüegg, Markus A. and Handschin, Christoph
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A. and Handschin, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13247
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (117 Seiten)
Language:English
Identification Number:
Last Modified:07 Sep 2019 04:30
Deposited On:06 Sep 2019 09:15

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