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Title: The importance of ERK5 for skeletal muscle development
Author: Carter, E. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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Analysis of mouse myoblasts during differentiation showed that ERK5 levels were up-regulated as soon as 12 hours, and ERK5 was specifically activated after 48 hours of differentiation, concomitant with activation of MEF2C. Furthermore, the presence of ERK5 in the nuclei of embryonic mouse muscle cells was shown, suggesting a role in muscle development. When ERK5 activity was increased in myoblasts there was an increase in MEF2C activation and myogenic fusion was enhanced, determined by expression of the muscle-specific genes myosin heavy chain (MHC) and myogenin. Conversely, when a kinase-dead dominant negative ERK5 was expressed, myoblasts showed decreased MEF2C activation and myogenic fusion. Perturbing ERK5 activity levels in this way did not affect proliferation, cell cycle exit or apoptosis of myoblasts, but increased ERK5 activity enhanced myoblast migration. IGF signalling is crucial in coordinating myogenesis. The hypothesis that ERK5 is involved in IGF mediated myogenic signalling was investigated. Addition of IGF-I to myoblasts increased ERK5 activation after 10 minutes, and resulted in ERK5GFP mutated at the activating phosphorylation residues was unable to relocate, demonstrating that phosphorylation of ERK5 is required for relocalisation. My data suggest that ERK5 is important for the formation of muscle tissue in the embryo and of fully differentiated myotubes in vitro, possibly through its interaction with IGF and MEF2C. Further work to delineate the signalling pathways leading to ERK5 activation during myogenesis may have therapeutic applications for muscle disorders such as the muscle-derived tumour rhabdomyosarcoma (RMS), where myoblasts are unable to fuse.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available