Journal Article

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3Beta

Tunin, Richard S, Van Eyk, Jennifer, Kooij, Viola, Witayavanitkul, Namthip, Kass, David A, Kirk, Jonathan A, Gao, Wei Dong, Holewinski, Ronald J, Agnetti, Giulio, de Tombe, Pieter P

2014

Overview

Cardiac resynchronization therapy (CRT), the application of biventricular stimulation to correct discoordinate contraction, is the only heart failure treatment that enhances acute and chronic systolic function, increases cardiac work, and reduces mortality. Resting myocyte function increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, in this paper, the authors examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HFdys) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3β (GSK-3β). They found that GSK-3β was deactivated in HFdys and reactivated by CRT. Mass spectrometry of myofilament proteins from HFdys animals incubated with GSK-3β confirmed GSK-3β-dependent phosphorylation at many of the same sites observed with CRT. These data indicate that CRT improves calcium responsiveness of myofilaments following HFdys through GSK-3β reactivation, identifying a therapeutic approach to enhancing contractile function.

• Publisher: American Society for Clinical Investigation
• Subject: Biomedical research / Dogs / Gene expression / Heart failure / Kinases / Phosphorylation / Proteins / Software / Studies