BACKGROUND The sarcomeric protein titin is a molecular spring responsible for passive tension and restoring forces of cardiomyocytes. Extension of titin as a function of sarcomere length (SL) has been studied in rodents, which predominantly express the smaller, stiffer N2B titin isoform. Large mammals coexpress roughly equal proportions of N2B and N2BA titin, the larger, more compliant isoform....

Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa). In its central I-band region, 47 novel PEVK exons were found, which contribute to titin’s extensible spring properties. Additionally,...

The sarcomeric Z-disk, the anchoring plane of thin (actin) filaments, links titin (also called connectin) and actin filaments from opposing sarcomere halves in a lattice connected by α-actinin. We demonstrate by protein interaction analysis that two types of titin interactions are involved in the assembly of α-actinin into the Z-disk. Titin interacts via a single binding site with the two centr...

The giant muscle protein titin, which provides a passive restoring force upon extension, is essential for maintaining the integrity of the muscular sarcomere. In order for titin to reversibly stretch and contract, the ends of this protein must be constrained, or anchored, at its terminal domains at the sarcomeric Z-disc and M-line. Here we investigate the role that telethonin, a protein which j...

The sliding filament theory of muscle contraction is widely accepted as the means by which muscles generate force during activation. Within the constraints of this theory, isometric, steady-state force produced during muscle activation is proportional to the amount of filament overlap. Previous studies from our laboratory demonstrated enhanced titin-based force in myofibrils that were actively ...

The sarcomeric Z-disk, the anchoring plane of thin (actin) filaments, links titin (also called connectin) and actin filaments from opposing sarcomere halves in a lattice connected by alpha-actinin. We demonstrate by protein interaction analysis that two types of titin interactions are involved in the assembly of alpha-actinin into the Z-disk. Titin interacts via a single binding site with the t...

Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains. Titin's M-line region contains a unique kinase domain that has been proposed to regulate sarcomere assembly via its substrate titin cap (T-cap). In this study, we use a titin M line-deficient mouse to show that the initial assembly of the sarcomere does...

Cardiac myofibrillogenesis was examined in cultured chick cardiac cells by immunofluorescence using antibodies against titin, actin, tropomyosin, and myosin. Primitive cardiomyocytes initially contained stress fiber-like structures (SFLS) that stained positively for alpha actin and/or muscle tropomyosin. In some cases the staining for muscle tropomyosin and alpha actin was disproportionate; thi...

H igh myocardial diastolic stiffness has usually been attributed to excessive myocardial collagen deposition. Over the last decennium, stiff cardiomyocytes were also identified as important contributors to high myocardial diastolic stiffness , especially in heart failure (HF) with preserved ejection fraction (HFPEF). Cardiomyocyte stiffness relates to elasticity of the giant cytoskeletal protei...

A direct titin-thick filament interaction in certain regions of the A band is suggested by results using four new monoclonal antibodies specific for titin in immunoelectron microscopy. Antibodies T30, T31 and T32 identify quasi-repeats in the titin molecule characterized by a 42-43 nm repeat spacing. These stripes seem to coincide with striations established by others on negatively stained cryo...