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Understanding the role of mTORC1 and mTORC2 in embryonic and adult myogenesis

Rion, Nathalie. Understanding the role of mTORC1 and mTORC2 in embryonic and adult myogenesis. 2017, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12559

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Abstract

Myogenesis describes the formation of skeletal muscle fibers during embryogenesis and their regeneration of injury in the adult. The formation of myofibers includes the commitment of cell progenitors into the muscle lineage, their amplification and subsequent differentiation and fusion into multi-nucleated myotubes. The mammalian target of rapamycin (mTOR) assembles into two distinct complexes, termed complex 1 (mTORC1) and 2 (mTORC2), and controls cellular growth and metabolism, in response to nutrients and extracellular signals. The mTOR signaling pathway is crucial for homeostasis of mature skeletal muscle and mTOR deregulation in muscle results in progressive myopathies. Since myogenesis is determined by a complex regulatory network involving growth factors and external stimuli, I investigated the function of mTOR signaling in embryonic and adult myogenesis.
This PhD thesis describes the role of mTORC1 and mTORC2 in embryonic and adult myogenesis using genetically modified mice. Depletion of raptor, an essential protein of mTORC1, in muscle progenitors caused the mice to die perinatally because of severe defects in muscle development. I observed that mTORC1 was highly active in embryonic muscle progenitors and precursors and became downregulated in differentiating and fusing myocytes, suggesting a predominant role in muscle cell commitment and proliferation. Accordingly, raptor-depleted myoblasts showed severe defects in proliferation, most probably caused by reduced rates of protein synthesis. Furthermore, loss of mTORC1 reduced, but did not abolish differentiation of myoblasts. Thus, the myogenic process was still completed, but less efficiently, in the absence of mTORC1. To investigate the role of mTORC1 in adult myogenesis, depletion of raptor was induced in adult muscle stem cells, called satellite cells. mTORC1 depletion did not affect the quiescence of satellite cells but delayed their activation upon external stimuli. Furthermore, I established that satellite cells deficient for raptor proliferated and differentiated less efficiently, resulting in poor regeneration following muscle injury.
Mice deficient for mTORC2 signaling in developing muscle were viable and showed no histological and functional alterations of skeletal muscle. Moreover, depletion of rictor in embryonic muscle progenitors did not affect the number of satellite cells and their myogenic function in adult skeletal muscle upon injury. In particular, rictor-depleted satellite cells did not differ from control cells in their proliferation, differentiation and fusion capacity. However, the number of satellite cells decreased following repeated muscle injuries in the absence of mTORC2. Furthermore, the number of quiescent satellite cells declined during physiological aging in mutant mice, causing an impairment in the regenerative capacity at progressed age.
In conclusion, I established that mTORC1, but not mTORC2 signaling is required for the formation of skeletal muscle during embryogenesis and for the regeneration of the tissue following severe muscle damage. I found that loss of mTORC1 reduces protein synthesis and thereby limits the proliferation and differentiation capacity of myoblasts during embryonic and adult myogenesis. In contrast, mTORC2 is dispensable for the myogenic function of myoblasts to proliferate, differentiate and fuse, but is required for the maintenance of the muscle stem cell pool during aging and after muscle injury. Overall, these results are of major importance as they extent our knowledge about the distinct roles of mTORC1 and mTORC2 in the myogenic process and the maintenance of the muscle stem cell pool. As mTOR is a central regulatory hub, integrating the metabolic status of a cell and translating those signals into proteostatic processes, my work has established that these mTOR-controlled functions are important in muscle precursors. These results may open new avenues regarding pathological conditions, such as aging or metabolic muscle disorders, which have also been related to mTOR deregulation.
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:12559
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (154 Blätter)
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:33
Deposited On:04 Apr 2018 13:51

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