Phosphorylation of titin modulates pas- sive stiffness of cardiac muscle in a titin

Question: How does phosphorylation of titan affect cardiac function? Background: Sarcomeres are the repeating contractile subunits from which the myofibrils of striated muscle are built. Titin is a large sarcomeric protein involved in muscle elasticity and myofibril scaffolding, which provides passive tension to muscle based on physiological demands. In mammalian cardiac tissue, there are two isoforms of titan that differ in the number of elastic elements (modules) in the sequence. Titin isoforms with fewer elastic elements (N2B) have increased passive tension, whereas isoforms with more elastic elements (N2BA) have decreased passive tension. -Adrenergic stimulation activates PKA to increase myocardial contractile force and accelerate relaxation. Although this is known to induce phosphorylation of a number of proteins, accumulating evidence suggests that -adrenergic modulation of myocardial properties involves, in part, myofilaments. Granzier and colleagues recently reported that -adrenergic stimulation of PKA causes phosphorylation of N2B, which reduces the passive (diastolic) force in cardiomyocytes, but the physiological role of titan phosphorylation in diastolic function is not well defined, and the role of titan phosphorylation in the active (systolic) cardiac function is unknown. Observations: In the current report, the effects of titan phosphorylation on diastolic and systolic function were explored. PKA-dependent phosphorylation was found to decrease both the restoring force and the passive force. The attenuated passive force involved phosphorylation of both N2B and N2BA but was more pronounced in tissues with higher N2B expression. The physiological relevance of the PKA-dependent phosphorylation was explored through -adrenergic stimulation, which decreases the diastolic force and increases titin phosphorylation. Significance: Fukuda et al. provide new mechanistic insight into how -adrenergic stimulation modulates diastolic and systolic function. The significance of this report is underscored by the observations that expression ratios of N2B and N2BA are altered in coronary artery disease and dilated cardiomyopathy, a disease in which the heart muscles become thin and flaccid and the heart becomes enlarged. Thus understanding how changes in titan isoform expression alter the functions of the heart has important implications for treating cardiac diseases.