The role of the epidermal growth factor signalling pathway in regulation of skeletal muscle fibre type

Abstract

Deranged skeletal muscle fibre type proportion is a common characteristic in a number of chronic diseases such as chronic obstructive pulmonary disease (COPD), cardiac failure, type 2 diabetes and obesity. In these conditions, there is a low quadriceps proportion of slow-twitch (ST) fibres, relative to fast-twitch (FT) fibres, associated with exercise limitation, insulin resistance, adiposity and, in COPD, mortality. Although skeletal muscle fibre types can switch and the benefits of increased ST fibre to exercise capacity, diabetes and obesity risk have been demonstrated in genetically modified animals, the molecular mechanisms regulating the switch between fibres are not completely understood. Therefore, at the present, druggable targets to increase ST fibre proportion are not available. Pathway analysis of microarray data from both COPD patients’ quadriceps (with high proportion of FT fibre) and published mouse data identified the EGF pathway to be associated with FT fibre phenotype, suggesting that the EGF pathway may be a suppressor of the ST fibre phenotype. My preliminary (MRes) data indicated that inhibition of the EGF-receptor (EGFR) in vitro promotes expression of ST fibre-associated genes, while suppressing FT fibre-associated gene expression. In this thesis, I aimed to consolidate the preliminary in vitro data and determine whether EGFR depletion promotes the ST phenotype in skeletal muscle in zebrafish (Danio rerio) and in mouse (Mus musculus). Pharmacological inhibition and EGFR silencing in vitro increased ST, including mitochondrial, gene and protein expression and increased glucose transporter 4 (GLUT4) transcripts. In zebrafish, egfra depletion by genome editing increased the number of ST fibres and mitochondrial content. In mice, pharmacological inhibition of EGFR increased GLUT4 gene expression in the tibialis anterior (TA). Together, these data indicate that EGFR may be involved in the regulation of the skeletal muscle fibre type gene expression and may play a role in chronic diseases characterised by deranged fibre type proportions.