Cardiac Titin and Heart Disease

Abstract

The giant sarcomeric protein titin is a key determinant of myocardial passive stiffness and stress sensitive signaling. Titin stiffness is modulated by isoform variation, phosphorylation by protein kinases and possibly oxidative stress through disulfide bond formation. Titin has also emerged as an important human disease gene. Early studies in patients with dilated cardiomyopathy (DCM) revealed shifts toward more compliant isoforms, an adaptation that offsets increases in passive stiffness based in the extracellular matrix. Similar shifts are observed in heart failure with preserved ejection fraction (HFpEF). In contrast, hypophosphorylation of PKA/G sites contributes to a net increase in cardiomyocyte resting tension in HFpEF. More recently, titin mutations have been recognized as the most common etiology of inherited DCM. In addition, some DCM-causing mutations affect RBM20, a titin splice factor. Titin mutations are a rare cause of hypertrophic cardiomyopathy (HCM) and also underlie some cases of arrhythmogenic right ventricular dysplasia. Finally, mutations of genes encoding proteins that interact with and/or bind to titin are responsible for both DCM and HCM. Targeting titin as a therapeutic strategy is in its infancy, but could potentially involve manipulation of isoforms, post-translational modifications, and up-regulation of normal protein in patients with disease causing mutations.

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

“…Another regulator, the giant molecule titin (Granzier and Irving, 1995;Granzier, 2013, 2014), extends through the A-band region, running from the Z-disc, to which actin filaments are bound, to the M-line, the center of the sarcomere. Thus, each half sarcomere has titin molecules running its entire length, where the titin plays an important role in passive tension of the sarcomere (Granzier and Irving, 1995) as well as other roles (LeWinter and Granzier, 2014). A recent report made the suggestion that MyBP-C and/or other proteins in the vicinity of the myosin heads may play a role in sequestering some of the heads and taking them out of the functionally available pool, reducing N t and thus F ensemble (Spudich, 2015).…”

Updating the Physiology and Pathophysiology of Cardiac Myosin-Binding Protein-C

“…Phosphorylation of these sites is reduced in DCM, which increases stiffness and offsets the isoform shift. 7 The net result seems to be a decrease in cardiomyocyte stiffness. Reduced phosphorylation of troponin I (TnI) and myosin regulatory light chain have also been reported in human DCM and are thought to contribute to impaired thin filament activation and contractility.…”

“…In this regard, it is of interest that PKA/PKG sites on titin are also hypophosphorylated. 7,13,14 Thus, β-adrenergic blockers, which are administered to many patients with HFpEF, could potentially worsen diastolic dysfunction by exacerbating hypophosphorylation of both proteins.…”

“…As in DCM, changes in titin isoforms and phosphorylation result in opposite effects on titin's stiffness, but in this case, changes in phosphorylation of titin's PKA/ PKG, as well as its PKC-α sites, are dominant and play a key role in markedly increased cardiomyocyte and myocardial passive stiffness. 7,13,14 Using permeabilized strips of human myocardium obtained from patients with hypertension and LVH and control subjects undergoing coronary bypass grafting, 15 all with normal EF, we recently reported that the crossbridge dissociation rate constant is slowed and its inverse, the cross-bridge on-time (time the cross-bridge is attached and generating force), is prolonged at submaximal [Ca 2+ ] in patients with hypertension+LVH compared with control subjects. These changes in acto-myosin dynamics serve to slow left ventricular relaxation.…”

More roles for the (passive) giant. Focus on “The increase in non-cross-bridge forces after stretch of activated striated muscle is related to titin isoforms”

“…Additionally, posttranslational modifications and calcium activation can regulate the degree of titin-derived static tension (3). The importance of titin to passive tension in muscle is evident in developmental and disease states, where changes in titin isoforms lead to consequential changes in muscle elastic properties (10). Because of its dynamic function in muscle physiology and pathophysiology, a number of recent studies have attempted to elucidate titin's role in the regulation of noncontractile force.…”