UC San Diego

Heart failure associated with advanced age is accompanied by molecular and cellular structural remodeling events within cardiomyocytes. One such event is remodeling of the cortical cytoskeleton by actin-binding molecules. Once thought to be a static compartment, the cardiac cytoskeleton is now known to be populated by mechanically- sensitive structural and signaling molecules. This dissertation concerns the role of the mechanosensitive protein vinculin in remodeling of cardiac cortical mechanics and explores its potential role in regulating contractile function with age. Age-related cardiac cytoskeletal reinforcement is shown to be an evolutionarily-conserved mechanism in simians, rats, and Drosophila melanogaster. Mechanistic studies show that cytoskeletal remodeling is correlated with preserved shortening velocity. Finally, cardiac-specific induction of cytoskeletal remodeling through overexpression of vinculin in both juvenile wildtype and myosin heavy chain knockdown flies led to enhanced shortening function and increased hemodynamic stress tolerance. Cytoskeletal reinforcement may play a protective role during aging in multiple cardiac systems by regulating myofilament organization and myocyte shortening