Our research is aimed at understanding the molecular mechanisms of muscle contraction through experimental work and modelling. Muscle contraction results from cyclical interaction of myosin motors in thick filaments with actin filaments within sarcomeres.
When operating as a motor, muscles convert chemical energy of ATP hydrolysis into mechanical work, thus generating the power required for our day-to-day activities; when cold, muscles also act as heat-generators ("shivering") in order to raise body temperature – indeed our work has shown that the power output in muscle is drastically reduced in cooling.
Another basic function of muscle is to operate as a “brake” and store energy, for example when an active muscle is lengthened by heavy external load or during eccentric exercise; an active muscle. Our recent research has focussed on this force increase during lengthening of active muscle and the experiments have raised a number of new questions. The force increase during lengthening is complex and is not much affected by myosin-ATPase inhibitors; also, the force rise induced by a rapid temperature-jump is inhibited during lengthening whereas it is enhanced during shortening.
Our working hypothesis is that ATPase cycle is inhibited (truncated) in lengthening muscle and processes other than actin-myosin motor interaction are involved. An equally important aspect of this work is to model this complex dynamic mechanical system. Two external collaborators, Dr Jachen Denoth and Ivo Telley (ETH, Zurich), have taken a theoretical approach to model the complexities of sarcomere dynamics, and Dr Gerald Offer is currently developing a realistic and comprehensive crossbridge model to simulate the observations.
Active force generation
Using rapid temperature- and pressure-jumps, we have shown that force-generating conformational change in myosin motor in muscle occurs in an endothermic step before the release of inorganic phosphate in the ATPase cycle, but the structural basis at a molecular level remains unclear.
Mechanism(s) of passive tension and visco-elasticity of resting muscle
Showed that molecular properties of titin can largely account for fibre type differences in resting tension behaviour.
Stretch -induced Ca-release and activation in neonatal muscle
Dr Gabriel Mutungi’s (previous Fellow in the group) work, collaborating with Prof Paul Edman (Sweden).
Temperature-dependence of Force-(shortening) Velocity relation
Jachen Denoth
Ivo Telley
ETH, Zurich
