Delineating Sarcomere Attributes Spanning Protein-Structure to Function to Tackle Cardiac Disease (Sarc-Attack)

The heart beats because every one of its cells contains tiny motors known as sarcomeres. Each motor is formed from thousands of proteins, like the many parts of a car engine. Sarcomeres are so small you could fit 300 into the tip of a ball-point pen. Thus, figuring out how sarcomeres are constructed and how their performance during each heart-beat is controlled has been very difficult. A big part of this challenge was recently overcome by advances in a method known as cryo-electron microscopy and tomography (cryo-EM and cryo-ET). This created never-before seen pictures of sarcomeres that explained how their native proteins fitted together. This was very important because most heart diseases have sarcomeres that do not work properly and, in many cases, this is because a protein is misshaped. Our group will be the first to study diseased hearts at this level. The SarcAttack Network brings together world-level experts in cardiology, cardiac and cell biophysics, cryo-EM and cryo-ET, X-ray crystallography, and computer modelling to study the structure and function of sarcomeres associated with two major forms of heart disease. We will study hearts with thick walls that contract too much and also hearts with thin walls that are weak and enlarged. Studies will use muscle samples donated by patients with either type of heart failure where a specific mutation is identified. Animals that express this same mutation will also be used for the studies. Lastly, we will test how new types of drugs change the way that sarcomeres work. One of our goals is to learn how to prescribe each patient with the most effective therapy. Our cutting-edge experiments will span from ultra-high resolution through to cell and intact heart function studies, all with the goal of better understanding why hearts fail and how best to fix them. Just as a mechanic needs to know how a car engine works before it can be fixed, we can only repair the heart’s sarcomeres if we fully understand how they are put together, how they function, and how diseases and drugs changes the underlying mechanisms.