Grant: Operating Grant

Titin is the third most abundant protein in muscles, and has been considered to have only passive structural roles until recently. However, in the past three years of CIHR support, we developed novel techniques that allowed us to study the properties of titin in completely new ways. By doing so, we discovered that titin increases its inherent stiffness and force when a muscle is activated, thereby contributing as much force to muscle contraction as the contractile proteins actin and myosin for some conditions. Since titin has also been shown to change its structure and function as a function of disease, injury, aging, disuse, and training, understanding its function, signaling, and force regulation in normal and diseased tissues has become a major thrust of scientific research in labs around the world. In this proposal, we want to identify the molecular mechanisms of force regulation by titin and study this force regulation in normal and diseased heart and skeletal muscles, where force regulation through titin appears disrupted. Understanding these mechanisms, we hope to define muscle diseases more accurately, understand the mechanical implications of disease, and hopefully, contribute to the design of treatment options for cardiac and skeletal muscle diseases.