Effect of Truncated Mutations in the Titin Gene on Cardiac Function

Abstract

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and impaired systolic function, where up to 40% of cases are associated with mutations. Truncating mutations in the TTN gene are the most common cause of familial DCM. While it is known that titin is the major contributor to myocardial stiffness and is an essential component of the Frank-Starling mechanism of the heart, its function is not fully established. Titin mechanical properties are particularly important in assisting with myofibril viscoelasticity and consequently contribute to the work output characteristic of myocardium. In contrast, changes in myofilament Ca2+-sensitivity and loss of its modulation by phosphorylation are involved in the proposed mechanism for disease-causing mutations in contractile proteins but not necessary in the TTN gene. We studied mechanical properties and isometric contractility in single cardiac myofibrils of DCM patients with and without TTN mutations. We found that all studied DCM mutations in contractile protein genes (TNNC1, TNNI3, and MYH7) including truncations in the titin gene (TTN), result in lower passive stiffness compared to donor samples. Furthermore we showed that the myofilament Ca2+-sensitivity was higher than donor and without any difference in myofibril kinetics. In fact, heart function is highly coordinated and strongly dependent on spatiotemporal control during the cardiac cycle so data obtained in isometric conditions may be inadequate to understand the effect of mutations. To further characterize mutations and the impact of myofibril length changes on cardiac output, we now use cyclic length and Ca2+ concentration changes to imitate the changes in single myofibril similar to those that have place during the cardiac work-producing cycle.