Activation of myocardial contraction by the N-terminal domains of myosin binding protein-C

T J Herron, E Rostkova, G Kunst, R Chaturvedi, M Gautel, J C Kentish

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80 Citations (Scopus)

Abstract

Myosin binding protein-C (MyBP-C) is a poorly understood component of the thick filament in striated muscle sarcomeres. Its C terminus binds tightly to myosin, whereas the N terminus contains binding sites for myosin S2 and possibly for the thin filament. To study the role of the N-terminal domains of cardiac MyBP-C (cMyBP-C), we added human N-terminal peptide fragments to human and rodent skinned ventricular myocytes. At concentrations > 10 mu mol/L, the N-terminal C0C2 peptide activated force production in the absence of calcium (pCa 9). Force at the optimal concentration (80 mu mol/L) of C0C2 was approximate to 60% of that in maximal Ca2+ ( pCa 4.5), but the rate constant of tension redevelopment (k(tr)) matched or exceeded (by up to 80%) that produced by Ca2+ alone. Experiments using different N-terminal peptides suggested that this activating effect of C0C2 resulted from binding by the pro/ala-rich C0-C1 linker region, rather than the terminal C0 domain. At a lower concentration (1 mu mol/L), exogenous C0C2 strongly sensitized cardiac myofibrils to Ca2+ at a sarcomere length (SL) of 1.9 mu m but had no significant effect at SL 2.3 mu m. This differential effect caused the normal SL dependence of myofibrillar Ca2+ sensitivity to be reduced by 80% ( mouse myocytes) or abolished ( human myocytes) in 1 mu mol/L C0C2. These results suggest that cMyBP-C provides a regulatory pathway by which the thick filament can influence the activation of the thin filament, separately from its regulation by Ca2+. Furthermore, the N-terminal region of cMyBP-C can influence the SL-tension ( Frank-Starling) relationship in cardiac muscle
Original languageEnglish
Pages (from-to)1290 - 1298
Number of pages9
JournalCirculation Research
Volume98
Issue number10
DOIs
Publication statusPublished - May 2006

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