Contemporary Reviews in Cardiovascular Medicine Cardiac Titin A Multifunctional Giant

Titin constitutes the third myofilament of cardiac muscle, with a single giant polypeptide spanning from the Z disk to the M-band region of the sarcomere1 (Figure 1). The 1.0-MDa region in the I band is extensible and consists of tandemly arranged immunoglobulin-like domains that make up proximal (near the Z disk) and distal (near the A-I junction) segments, interspersed by the PEVK sequence (rich in proline, glutamate, valine, and lysine residues) and the N2B element.2 Each functions as a distinct spring element.3 The C-terminal 2 MDa of titin is located in the A band and is inextensible. It is composed of regular arrays of immunoglobulin and fibronectin type 3 modules that form so-called super-repeats.2 A-band titin may function as a molecular ruler, regulating assembly of the thick filament.2,4,5 The 250-kDa COOH-terminal region of titin is an integral part of the M band and contains a kinase domain.6,7 As in the Z disk, where titin filaments from opposite sarcomeres overlap, titin filaments from opposite half-sarcomeres overlap within the M band, where they are interconnected by M-band proteins.8 Thus, titin filaments with opposite polarity overlap in both Z disk and M band, forming a contiguous filament along the myofibril. In this review, we discuss the functions of titin in the heart, with an emphasis on its role in diastolic function and the various mechanisms whereby passive stiffness can be tuned. Because of space constraints, it has not been possible to provide inclusive references to all original articles in the field.