title: Cross-bridge versus thin filament contributions to the level and rate of force development in cardiac muscle.
abstract: In striated muscle thin filament activation is initiated by Ca(2+) binding to troponin C and augmented by strong myosin binding to actin (cross-bridge formation). Several lines of evidence have led us to hypothesize that thin filament properties may limit the level and rate of force development in cardiac muscle at all levels of Ca(2+) activation. As a test of this hypothesis we varied the cross-bridge contribution to thin filament activation by substituting 2 deoxy-ATP (dATP; a strong cross-bridge augmenter) for ATP as the contractile substrate and compared steady-state force and stiffness, and the rate of force redevelopment (k(tr)) in demembranated rat cardiac trabeculae as [Ca(2+)] was varied. We also tested whether thin filament dynamics limits force development kinetics during maximal Ca(2+) activation by comparing the rate of force development (k(Ca)) after a step increase in [Ca(2+)] with photorelease of Ca(2+) from NP-EGTA to maximal k(tr), where Ca(2+) binding to thin filaments should be in (near) equilibrium during force redevelopment. dATP enhanced steady-state force and stiffness at all levels of Ca(2+) activation. At similar submaximal levels of steady-state force there was no increase in k(tr) with dATP, but k(tr) was enhanced at higher Ca(2+) concentrations, resulting in an extension (not elevation) of the k(tr)-force relationship. Interestingly, we found that maximal k(tr) was faster than k(Ca), and that dATP increased both by a similar amount. Our data suggest the dynamics of Ca(2+)-mediated thin filament activation limits the rate that force develops in rat cardiac muscle, even at saturating levels of Ca(2+).
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA. mregnier@u.washington.edu
authors.forename: M
authors.initials: M
authors.lastname: Regnier
authors.forename: H
authors.initials: H
authors.lastname: Martin
authors.forename: R J
authors.initials: RJ
authors.lastname: Barsotti
authors.forename: A J
authors.initials: AJ
authors.lastname: Rivera
authors.forename: D A
authors.initials: DA
authors.lastname: Martyn
authors.forename: E
authors.initials: E
authors.lastname: Clemmens
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004533:Egtazic Acid / Q000737:chemistry; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013997:Time Factors; D014335:Tropomyosin / Q000737:chemistry; D019209:Troponin C / Q000737:chemistry
chemical_list: D014335:Tropomyosin; D019209:Troponin C; D004533:Egtazic Acid; D000255:Adenosine Triphosphate; D002118:Calcium