Thesis--Københavns universitet. / Bibliography: p. [248]-255.

Thesis--Københavns universitet. / Bibliography: p. [248]-255.

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.

"May 2002." Bibliography: leaves 123-144. Aspects of the control of ventilation and an upper airway dilator muscle (genioglossus) are compared between healthy men and women, in an attempt to identify a gender difference that may contribute to the high male prevalence of sleep apnea.

[Truncated abstract] The extent to which an airway narrows is strongly influenced by mechanical loads on airway smooth muscle (ASM). This thesis considers both dynamic and static mechanical loads. Dynamic load describes the time varying load on airways produced by oscillatory breathing movements. Static load is that present at a fixed lung volume ie. without breathing. In the intact lung static load principally comprises the pressure across the airway wall, that is transmural pressure (Ptm), and elastic after-load arising from distortion of airway and lung tissue by the narrowing airway. The experiments performed in this thesis were designed to answer several outstanding questions relating to how dynamic and static loads regulate airway narrowing. Dynamic load from breathing movements cyclically stretches ASM, which produces a number of physiological and cellular effects. For example in ASM strips a period of cyclical stretch reduces subsequent ASM contraction. However the response of the whole airway to dynamic load may differ from isolated ASM where non-muscle tissue also contributes. The first aim of this thesis was to characterise the response of the whole airway to dynamic load and determine whether the airway wall modifies the effects produced by ASM length cycling. Static after-loads restrict ASM shortening providing a limit to airway narrowing. Two primary sources of airway wall load include cartilage and the mucosal membrane which contribute to airway compliance. The relative importance of cartilage and mucosa to airway wall compliance and airway narrowing is unclear. ... Results demonstrate that airway narrowing is restricted by Ptm but not by parenchymal elastic after-load. The major findings of this thesis are: (1) dynamic loads produced by breathing movements regulate airway responsiveness through cyclical airway expansion and elongation; (2) the reported effects of cyclical stretch on ASM contraction differs in situ 8 possibly due to modification by one or more biomechanical or physiological properties of the airway wall; (3) parenchymal elastic after-loads, previously thought to be important during bronchoconstriction, do not restrict airway narrowing. Given the absence of an effect of parenchymal elastic after-load on airway narrowing, the static mechanical load on ASM therefore comprises Ptm and airway wall stiffness, with important contributions from cartilage and mucosa depending on lung volume.

"May 2002." / Bibliography: leaves 123-144. / xiv, 144 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aspects of the control of ventilation and an upper airway dilator muscle (genioglossus) are compared between healthy men and women, in an attempt to identify a gender difference that may contribute to the high male prevalence of sleep apnea. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2002