Grant: Operating Grant

For the past fifty years, muscle contraction has been assumed to be exclusively governed by the contractile proteins actin and myosin. However, recent experiments from our group demonstrate that titin, a structural protein so far believed to play a purely passive role in muscles, is likely to regulate active forces too. Furthermore, it is well accepted that titin functionally adapts in muscle diseases and muscle degeneration as observed for example in heart disease, such as cardiac myopathies, and in muscle degeneration associated with aging, injury, disuse and Botox treatments. In this proposal we try to achieve two goals: first, we would like to demonstrate directly how titin regulates force in contracting muscles. This will be done by quantifying titin elongations under passive (no calcium) and active (high calcium) stretch conditions, which will provide insight into titin's possible interactions with the contractile protein actin and its force and stiffness regulation in the presence of calcium. Second, we would like to identify how titin produces the dramatic passive forces measured in spastic muscles from cerebral palsy children. The experiments will be performed on single myofibril preparations that are stretched under active and passive conditions, and on isolated titin segments using atomic force microscopy. These experiments will provide novel insight into force regulation in normal and diseased (cerebral palsy) muscles and will shed light into titin's role in muscle force regulation and cardiac and skeletal muscle diseases.