Molecular bases of regulation of cardiac muscle contractility

Regulation of muscle contraction is operated by both thin, actin containing filaments, and thick, myosin containing filaments. Ca2+-induced structural changes in the regulatory proteins of the thin filament release the actin sites for interaction with myosin. Thick filament mechanosensing adapts to the load the number of motors switched ON from the resting (OFF) state. In the heartbeat the internal [Ca2+] does not saturate and both Ca-sensitivity and thick filament mechanosensing are under the control of several modulatory mechanisms, like the degree of phosphorylation of sarcomeric proteins. Mutations in these proteins cause dysregulation and cardiomyopathy. Using X-ray diffraction on intact heart trabeculae we study the role of the sarcomeric proteins in the interfilament communication and in the mechanosensing that control the systolic performance and cause its dysregulation in cardiomyopathies, and test the effect of small molecules candidate as therapeutic tools.