Molecular bases of regulation of cardiac muscle contractility

Regulation of muscle contraction is due to mechanisms on both thin and thick filaments. Ca2+-induced structural changes in the regulatory proteins on the thin filament allow the myosin motors to attach to actin. Thick filament regulation is based on a still undefined mechanosensor that adapts to the load of the contraction the number of motors switched ON from the resting (OFF) state, in which they lie on the thick filament. In the heartbeat the internal [Ca2+] transient may not attain saturation and Ca2+-sensitivity of the filament is a relevant parameter under the control of several modulatory mechanisms, like the length dependent activation and the degree of phosphorylation of sarcomeric proteins. Mutations in these proteins cause dysregulation and cardiomyopathy. Using X-ray diffraction on intact heart trabeculae we define the role of the sarcomeric proteins in the interfilament communication and in the mechanosensing that controls the switching ON of the myosin motors.