Fellowship/Kelly-Senetar: Talin-1 and Talin-2 in Muscle Differentiation

The ability of a cell to sense and respond to changes in its physical environment is due to a series of dynamic interactions between a cell, its extracellular matrix (ECM), and the intracellular actin cytoskeleton. These cell-ECM interactions are crucial to myogenesis and proper muscle cell assembly. In cardiac and skeletal muscle, these interactions are governed by distinct macromolecular complexes including focal adhesions, costameres, and intercalated disks. The cytoskeletal anchor protein talin serves as an essential link between the cytoplasm and the ECM in all these structures. Talin is a large (>2500 aa), modular protein that consists of an N-terminal FERM domain, a long, helical rod domain, and a C-terminall/LWEQ module. Although a number of physiological binding partners for talin have been identified, the precise roles of talin in muscle physiology have yet to be determined. In addition, we have recently identified a second talin gene. Thus, prior studies of talin have misinterpreted the action of two unique molecules. The long-term goals of this research are to gauge how cell-ECM interactions are involved in the development and maintenance of cardiac and skeletal muscle. In this proposal, we have outlined a series of experiments designed to understand the mechanisms by which the isoforms of talin, Talin-1 and Talin-2 (Tn-1/2), contribute to striated muscle differentiation and muscle cell architecture. As the proper assembly of talin-containing complexes is required for myogenesis and striated muscle organization, knowledge of how Tn-1/2 contribute to these processes is critical to understand how dysregulation of adhesion complexes and cytoskeletal alterations contribute to heart failure and cardiovascular disease. We anticipate that the research outlined here will provide a molecular basis to understand several cardiac and skeletal myopathies, which may lead to approaches to combat these diseases by modulation of talin-containing adhesion complexes.