Talin Isoforms and Myogenesis

The interactions between muscle cells and the extracellular environment are critical to myogenesis and the establishment of muscle cell architecture. These interactions are mediated primarily by costameres and focal adhesion complexes, which are large, multicomponent assemblies that link the extracellular matrix through integrins to the muscle cell cytoskeleton. The long-term objectives of this application are to understand how these interactions are involved in the development of cardiac and skeletal muscle. The primary focus of this research proposal is the large, modular protein talin, which is a fundamental component of both costameres and focal adhesions. Talin is required for the formation of focal adhesions, cell adhesion, and cell motility. These processes are fundamental to cell physiology. Although a number of physiological partners of talin have been identified, the exact rol.esof talin in costamere and focal adhesion formation have not been identified. Moreover, the recent discovery of a differentially expressed second talin gene and the identification of alternatively processed variants of this gene demonstrate that talin function is actually due to the action of several proteins. These talin isoforms are differentially expressed during myogenesis. The specific objectives of this proposal are to characterize the physiological roles of the talin isoforms Talin-1 and Talin-2 in myogenesis. This will be accomplished first characterizing the differential expression patterns of Talin-1 and Talin-2 during myogenesis. Biochemical, proteomics, and molecular genetic approaches will then be used to identify talin isoform-specific physiological partners. Correlation of the results of these approaches will establish the roles of Talin-1 and Talin-2 as components of multicomponent assemblies in cardiac and skeletal muscle myogenesis. Disruption of the interactions mediated by membrane-associated cytoskeletal complexes leads to pathological conditions such as dilated cardiomyopathy, cardiac hypertrophy, and muscular dystrophy. Therefore, we anticipate that the research outlined in this application will contribute to our understanding of the molecular and cellular bases of these and similar conditions. This knowledge may then suggest approaches, by modulation of talin-containing multi-protein complexes, to the prevention or amelioration of these devastating muscle diseases.