Michael Gotthardt’s lab at the MDC, in collaboration with scientists at Washington State University (US), has now uncovered a key role that one of these modules plays in the development and function of the heart. Their work appears in the Feb. 27 edition of the journal PNAS.
Titin links the components of sarcomeres, long rows of piston-like structures within muscle tissues. It acts as a “spring” and is thought to help monitor the stress placed on sarcomeres as they expand and contract, but how the protein accomplishes this has not been known. One hypothesis suggested that a module called N2B – only found in titin in heart muscle – plays a role. Mutations in this part of the protein have been discovered in people who suffer from cardiac dilation or hypertrophy – diseases in which the chamber or the wall of the heart is enlarged. The problems are thought to arise partly because mutations disturb communication between titin and another protein called FHL2.
To get an idea of N2B’s functions, Michael Radke and other members of the lab developed a strain of mouse with a version of titin that lacked the module. The mice survived and appeared healthy, but closer study showed that their sarcomeres were shorter and their hearts were smaller than normal. They took in less blood, and the muscles in their walls experienced more stress. But the heart compensates by beating faster or pumping blood more efficiently.
The scientists examined muscle tissue under the microscope to learn why the missing module was changing heart structure. N2B was thought to act as an extra spring within titin, meaning that other modules in the protein did not have to unfold during the piston-like movement of the sarcomeres. Without N2B those regions were forced to unfold, and the pistons could not slide as far. Another discovery was that heart cells were not producing as much FHL2. This protein is thought to pass along information that helps the heart grow to its proper size.
Gotthardt says that the study has two important results. First, it gives new insights into the role that the body’s largest protein plays in determining the length of the sarcomere and the elastic properties of the heart. Secondly, mice without N2B provide scientists with the first genetic animal model to study conditions in which the heart does not sufficiently fill with blood during the relaxation phase. These types of problems most commonly affect female patients suffering from cardiac disease. Both findings should help researchers in understanding the causes of such diseases and intervening, possibly even using titin as a target for therapies.
Michael H. Radke*, Jun Peng†, Yiming Wu†, Mark McNabb†, O. Lynne Nelson‡, Hendrikus Granzier†, and Michael Gotthardt*†§ *Department of Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, D-13122 Berlin-Buch, Germany; and †Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, and §Department of Veterinary Clinical Sciences, Washingston State University, Pullman, WA 99164