Coupling of adjacent tropomyosins enhances cross-bridge-mediated cooperative activation in a markov model of the cardiac thin filament.

Stuart G. Campbell, Fred V. Lionetti, Kenneth S. Campbell, Andrew D. McCulloch

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

We developed a Markov model of cardiac thin filament activation that accounts for interactions among nearest-neighbor regulatory units (RUs) in a spatially explicit manner. Interactions were assumed to arise from structural coupling of adjacent tropomyosins (Tms), such that Tm shifting within each RU was influenced by the Tm status of its neighbors. Simulations using the model demonstrate that this coupling is sufficient to produce observed cooperativity in both steady-state and dynamic force-Ca(2+) relationships. The model was further validated by comparison with reported responses under various conditions including inhibition of myosin binding and the addition of strong-binding, non-force-producing myosin fragments. The model also reproduced the effects of 2.5 mM added P(i) on Ca(2+)-activated force and the rate of force redevelopment measured in skinned rat myocardial preparations. Model analysis suggests that Tm-Tm coupling potentiates the activating effects of strongly-bound cross-bridges and contributes to force-Ca(2+) dynamics of intact cardiac muscle. The model further predicts that activation at low Ca(2+) concentrations is cooperatively inhibited by nearest neighbors, requiring Ca(2+) binding to >25% of RUs to produce appreciable levels of force. Without excluding other putative cooperative mechanisms, these findings suggest that structural coupling of adjacent Tm molecules contributes to several properties of cardiac myofilament activation.

Original languageEnglish
Pages (from-to)2254-2264
Number of pages11
JournalBiophysical Journal
Volume98
Issue number10
DOIs
StatePublished - May 19 2010

Bibliographical note

Funding Information:
This study was supported by an American Heart Association predoctoral fellowship (to S.G.C.), the National Biomedical Computation Resource (National Institutes of Health grant P41 RR08605, to A.D.M), and the National Science Foundation (grant BES-0506252 to A.D.M) and the National Heart, Lung and Blood Institute (grant 1 R01 HL096544 to A.D.M.). This investigation was conducted in part using a facility constructed with support from Research Facilities Improvement Program grant C06 RR-017588-01 from the National Center for Research Resources, National Institutes of Health.

ASJC Scopus subject areas

  • Biophysics

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