Published online before print September 6, 2007, doi: 10.1161/CIRCRESAHA.107.158774
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Submitted on March 2, 2007
Revised on August 22, 2007
Accepted on August 29, 2007
Cardiac Myosin-Binding Protein C Is Required for Complete Relaxation in Intact Myocytes
Lutz Pohlmann ;
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, F-75013, France; the University Pierre et Marie Curie-Paris6 (N.V., L.C.), UMR S582, IFR14, Paris, F-75013, France; Inserm, U689 (C.C.), Cardiovascular Research Center, Paris, F-75010, France; and the Department of Physiology (S.W.), University of Pennsylvania School of Medicine, Philadelphia.
* To whom correspondence should be addressed. 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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