The role of contraction in skeletal muscle development

Abstract

The aim of this project was to determine the role of contraction in skeletal muscle development. The role of the initial spontaneous contractions observed in zebrafish embryos from 17 to 24 hours post fertilisation was examined. Genetic and pharmacologic approaches were used to study paralysis-induced disruption of skeletal muscle structure and function and subsequently determine the role of contraction. The structural and functional characteristics of developing skeletal muscles were found to be regulated by a dual mechanism of both movement-dependent and independent processes, in vivo. Novel data demonstrates that contraction controls sarcomere remodelling, namely regulation of actin length, via movement driven localisation of the actin capping protein, Tropmodulin1. Myofibril length was also shown to be linked to the mechanical passive property, stretch, with lengthening leading to an increase of the muscle’s ability to stretch. In addition, myofibril bundling and the myofilament lattice spacing, responsible for active tension generation via cross-bridge formation, were shown to be unaffected by paralysis and thus, movement-independent processes. Furthermore, the mechanism of the contraction-driven myofibril organisation pathway at the focal adhesion complexes (FAC), was shown to be different in zebrafish compared to mammals, with mechanosensing revolving around the Src protein rather than Fak. In summary, the role of contraction was established as a critical driver of myofibril organisation and passive tension in the developing zebrafish skeletal muscle. Passive tension regulates muscle function by determining its operational range ensuring that the needs of locomotion are met. Furthermore, investigation of FAC’s role in the contractiondriven myofibril organisation pathway led to the discovery of a novel function for Src in zebrafish somitogenesis. These two findings (i) that contraction is a driver of myofibril organisation and (ii) that Src is a key protein of the skeletal muscle development provides the potential for new therapeutic approaches in humans.