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(Circulation Research. 2007;101:928.)
© 2007 American Heart Association, Inc.

Cellular Biology

Cardiac Myosin-Binding Protein C Is Required for Complete Relaxation in Intact Myocytes

Lutz Pohlmann, Irena Kröger, Nicolas Vignier, Saskia Schlossarek, Elisabeth Krämer, Catherine Coirault, Karim R. Sultan, Ali El-Armouche, Saul Winegrad, Thomas Eschenhagen, Lucie Carrier

From the Institute of Experimental and Clinical Pharmacology and Toxicology (L.P., I.K., S.S., E.K., K.R.S., A.E.A., T.E., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Inserm, U582 (N.V., L.C.), Institut de Myologie, Paris, France; the University Pierre et Marie Curie-Paris6 (N.V., L.C.), UMR S582, IFR14, Paris, France; Inserm, U689 (C.C.), Cardiovascular Research Center, Paris, France; and the Department of Physiology (S.W.), University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Lucie Carrier, PhD, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany. E-mail l.carrier{at}uke.uni-hamburg.de

The role of cardiac myosin-binding protein C (cMyBP-C) in cardiac contraction is still not fully resolved. Experimental ablation of cMyBP-C by various means resulted in inconsistent changes in Ca²⁺ sensitivity and increased velocity of force of skinned preparations. To evaluate how these effects are integrated in an intact, living myocyte context, we investigated consequences of cMyBP-C ablation in ventricular myocytes and left atria from cMyBP-C knock-out (KO) mice compared with wild-type (WT). At 6 weeks, KO myocytes exhibited mild hypertrophy that became more pronounced by 30 weeks. Isolated cells from KO exhibited markedly lower diastolic sarcomere length (SL) without change in diastolic Ca²⁺. The lower SL in KO was partly abolished by the actin-myosin ATPase inhibitors 2,3-butanedione monoxime or blebbistatin, indicating residual actin-myosin interaction in diastole. The relationship between cytosolic Ca²⁺ and SL showed that KO cells started to contract at lower Ca²⁺ without reaching a higher maximum, yielding a smaller area of the phase-plane diagram. Both sarcomere shortening and Ca²⁺ transient were prolonged in KO. Isolated KO left atria exhibited a marked increase in sensitivity to external Ca²⁺ and, in contrast to WT, continued to develop twitch force at low micromolar Ca²⁺. Taken together, the main consequence of cMyBP-C ablation was a defect in diastolic relaxation and a smaller dynamic range of cell shortening, both of which likely result from the increased myofilament Ca²⁺ sensitivity. Our findings indicate that cMyBP-C functions as a restraint on myosin-actin interaction at low Ca²⁺ and short SL to allow complete relaxation during diastole.

Key Words: cardiac myocytes • contraction • familial hypertrophic cardiomyopathy • hypertrophy • transgenic mice

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