The Irving group investigates molecular mechanisms of contraction and its regulation in skeletal muscle and in the heart. Both types of tissue generate force and shortening by the relative sliding between the myosin-containing thick filaments and the actin-containing thin filaments. We developed a novel in situ X-ray and fluorescence techniques to measure the dynamic changes in protein conformation that drive muscle cell function. We used those methods to measure the size and speed of the working stroke in the myosin motors that drive contraction and the force per myosin molecule, and showed that these molecular parameters provided a quantitative explanation of muscle function at the cellular level.
Contraction of both skeletal and heart muscle is triggered by excitation of the cell membrane, which triggers the release of calcium ions that bind to the regulatory protein troponin, causing a structural change in the thin filaments that allows the myosin motors to bind to them. We characterized these structural changes in troponin in muscle cells and showed that they are much faster than force development. We extended these studies to describe the mechanism of action of drugs that bind to troponin used in the treatment of heart disease and troponin mutations associated with hypertrophic cardiomyopathy.
Recently the focus of our work on muscle regulation switched to previously neglected 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 unavailable for interaction with actin. We showed how this OFF state is modulated by physiological control pathways involving myosin binding protein-C and the myosin regulatory light chain. We also described a novel mechano-sensing mechanism in the thick filaments that link the mobilization of the motors to the external load on the muscle- the ‘automatic gearbox’ of muscle.
It now seems clear that thick filament regulation, although largely neglected for 40 years and still largely omitted from textbook descriptions, is of fundamental significance for controlling the strength and speed of contraction and relaxation in both skeletal and heart muscle. We are currently investigating the mechanisms that link thick filament regulation to the well-known thin filament-based regulatory pathways, the functional consequences of mutations in thick filament proteins associated with heart disease, and potential therapeutics for heart disease that might target those mechanisms.
Current PhD students:
We are currently recruiting for two post-docs and a research technician.