The Irving Group
The Irving group aims to elucidate molecular mechanisms of contraction and its regulation in skeletal and cardiac muscle. Both types of muscle generate force and shortening by the relative sliding between the myosin-containing thick filaments and the actin-containing thin filaments. In vitro structural studies led to a model in which filament sliding is driven by tilting of the light-chain domain of myosin in a ‘working stroke’. We developed novel X-ray and fluorescence techniques (see methods and protocols) and used them to test this model in isolated skeletal muscle cells. We measured the size and speed of the working stroke and the force per myosin, and showed that these molecular parameters provided a quantitative explanation of muscle function at the cellular level.
Contraction of an individual muscle cell is switched on by an electrical signal in its motor nerve, which triggers the release of calcium ions in the muscle cell. These calcium ions bind to the thin filament regulatory protein troponin, causing a structural change in the thin filaments that allows the myosin motors to bind to them. We have characterized the changes in troponin structure associated with calcium signaling, and correlated these changes with the mechanical response to the calcium transient. We extended these studies to describe the mechanism of action of drugs that bind to troponin that are used to treat heart disease, and troponin mutations associated with hypertrophic cardiomyopathy.
Recently the focus of our work on muscle regulation has switched to the less well-understood mechanisms involving thick filament proteins. We characterized an OFF state of the thick filament in which the motor domains of myosin are parked on the surface of the filaments and are therefore unavailable for interaction with actin. We showed how this OFF state is modulated by physiological control pathways involving myosin binding protein C and phosphorylation of the myosin regulatory light chain. We also described a novel mechano-sensing mechanism in the thick filaments that links the mobilization of the motors to the external load on the muscle- its ‘automatic gearbox’.
Currently we are extending these studies and concepts to elucidate the molecular mechanisms of thick filament regulation in skeletal and heart muscle, their links to the well-known thin filament-based regulatory pathways, and the functional consequences of mutations in these thick filament proteins associated with heart disease.
- Professor Malcolm Irving, FRS (Group Leader)
- Dr Elisabetta Brunello- Postdoctoral Research Associate
- Dr Luca Fusi- Postdoctoral Research Associate
- Dr Thomas Kampourakis – BHF Intermediate fellow
- Miss Ziqian Yan – Research Technician