Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium

Regis R. Lamberts, Nazha Hamdani, Tenoedj W. Soekhoe, Nicky M. Boontje, Ruud Zaremba, Lori A. Walker, Pieter P. De Tombe, Jolanda Van Der Velden, Ger J.M. Stienen

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Abstract

The positive force-frequency relation, one of the key factors modulating performance of healthy myocardium, has been attributed to an increased Ca2+ influx per unit of time. In failing hearts, a blunted, flat or negative force-frequency relation has been found. In healthy and failing hearts frequency-dependent alterations in Ca2+ sensitivity of the myofilaments, related to different phosphorylation levels of contractile proteins, could contribute to this process. Therefore, the frequency dependency of force, intracellular free Ca2+ ([Ca2+]i), Ca2+ sensitivity and contractile protein phosphorylation were determined in control and monocrotaline-treated, failing rat hearts. An increase in frequency from 0.5 to 6 Hz resulted in an increase in force in control (14.3 ± 3.0 mN mm-2) and a decrease in force in failing trabeculae (9.4 ± 3.2 mN mm-2), whereas in both groups the amplitude of [Ca2+]i transient increased. In permeabilized cardiomyocytes, isolated from control hearts paced at 0 and 9 Hz, Ca2+ sensitivity remained constant with frequency (pCa50: 5.55 ± 0.02 and 5.58 ± 0.01, respectively, P > 0.05), whereas in cardiomyocytes from failing hearts Ca2+ sensitivity decreased with frequency (pCa 50: 5.62 ± 0.01 and 5.57 ± 0.01, respectively, P < 0.05). After incubation of the cardiomyocytes with protein kinase A (PKA) this frequency dependency of Ca2+ sensitivity was abolished. Troponin I (TnI) and myosin light chain 2 (MLC2) phosphorylation remained constant in control hearts but both increased with frequency in failing hearts. In conclusion, in heart failure frequency-dependent myofilament Ca2+ desensitization, through increased TnI phosphorylation, contributes to the negative force-frequency relation and is counteracted by a frequency-dependent MLC2 phosphorylation. We propose a novel role for PKC-mediated TnI phosphorylation in modulating the force-frequency relation.

Original languageEnglish
Pages (from-to)695-709
Number of pages15
JournalJournal of Physiology
Volume582
Issue number2
DOIs
Publication statusPublished - 1 Jul 2007

Cite this

Lamberts, R. R., Hamdani, N., Soekhoe, T. W., Boontje, N. M., Zaremba, R., Walker, L. A., ... Stienen, G. J. M. (2007). Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium. Journal of Physiology, 582(2), 695-709. https://doi.org/10.1113/jphysiol.2007.134486