Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3beta Journal Article

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Authors: Kirk, J. A.; Holewinski, R. J.; Kooij, V.; Agnetti, G.; Tunin, R. S.; Witayavanitkul, N.; de Tombe, P. P.; Gao, W. D.; Van Eyk, J.; Kass, D. A.
Article Title: Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3beta
Abstract: 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 also increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, we examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HF(dys)) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Compared with control, maximal calcium-activated force and calcium sensitivity declined globally in HF(dys); however, CRT restored both. Phosphatase PP1 induced calcium desensitization in control and CRT-treated cells, while HF(dys) cells were unaffected, implying that CRT enhances myofilament phosphorylation. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3beta (GSK-3beta). We found that GSK-3beta was deactivated in HF(dys) and reactivated by CRT. Mass spectrometry of myofilament proteins from HF(dys) animals incubated with GSK-3beta confirmed GSK-3beta-dependent phosphorylation at many of the same sites observed with CRT. GSK-3beta restored calcium sensitivity in HF(dys), but did not affect control or CRT cells. These data indicate that CRT improves calcium responsiveness of myofilaments following HF(dys) through GSK-3beta reactivation, identifying a therapeutic approach to enhancing contractile function
Journal Title: The Journal of clinical investigation
Volume: 124
Issue: 1
ISSN: 1558-8238; 0021-9738
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: 129
End Page: 138
Language: eng
DOI/URL:

69253
Notes: LR: 20140319; GR: HHSN268201000032C/PHS HHS/United States; GR: HL62426/HL/NHLBI NIH HHS/United States; GR: HV-10-05/HV/NHLBI NIH HHS/United States; GR: P01 HL062426/HL/NHLBI NIH HHS/United States; GR: P01-HL077180/HL/NHLBI NIH HHS/United States; GR: R01 HL075494/HL/NHLBI NIH HHS/United States; GR: T32 HL007227/HL/NHLBI NIH HHS/United States; GR: T32-HL007227/HL/NHLBI NIH HHS/United States; JID: 7802877; 0 (Troponin I); 0 (Troponin T); EC 2.7.11.26 (Glycogen Synthase Kinase 3); SY7Q814VUP (Calcium); OID: NLM: PMC3871225; 2013/02/08 [received]; 2013/09/19 [accepted]; ppublish