Project 443890

Textbooks of muscle physiology state that muscle contraction and force production are entirely accounted for by two proteins, actin and myosin. This actin and myosin-based theory was developed in the mid-1950 by Nobel Prize winner Andrew Huxley, and it has remained unchallenged for the past half century. However, in 2002, we discovered a new mechanical property of muscle, referred to as "passive force enhancement". This property allows muscles to produce much more force at a lower energetic cost than can be accounted for by the actin-myosin theory. We identified that this additional, unexplained force was contributed by a structural protein called "titin". However, despite extensive research in this newly discovered area of muscle physiology and mechanics over the past decade, it remains unclear how titin produces this unexplained extra force. The primary objective of our research is to determine the molecular details of titin's function and its contribution to muscle contraction and force production. Ten years ago, we proposed a mechanism for titin's function in muscle contraction that has become the most accepted theory because of its simplicity and intuitive appeal. We hypothesized that titin increases its stiffness when a muscle is activated in two ways: (i) by binding calcium to specific sites thereby reinforcing its molecular bonds, and (ii) by titin's proximal segments binding to actin, thus decreasing titin's spring length and thus making it stiffer. The first of these mechanisms has been proved correct, the second is the topic of the research proposed here. Recently genetic changes in titin's structure have been associated with skeletal muscle diseases (dystrophies) and with many cardiac myopathies (heart diseases and heart failures), particularly those associated with an unnatural expansion of the heart. Understanding titin's function in normal muscles and hearts might help treat/prevent some of the skeletal and heart muscle diseases in the future.