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* Department of Bioengineering, University of Washington, Seattle, Washington 98195; and Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
Correspondence: Address reprint requests to Michael Regnier, Dept. of Bioengineering, Box 357962, School of Medicine, University of Washington, Seattle, WA 98195-7962. Tel.: 206-616-4325; Fax: 206-685-3300; E-mail: mregnier{at}u.washington.edu.
In striated muscle thin filament activation is initiated by Ca2+ 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 Ca2+ 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 (ktr) in demembranated rat cardiac trabeculae as [Ca2+] was varied. We also tested whether thin filament dynamics limits force development kinetics during maximal Ca2+ activation by comparing the rate of force development (kCa) after a step increase in [Ca2+] with photorelease of Ca2+ from NP-EGTA to maximal ktr, where Ca2+ binding to thin filaments should be in (near) equilibrium during force redevelopment. dATP enhanced steady-state force and stiffness at all levels of Ca2+ activation. At similar submaximal levels of steady-state force there was no increase in ktr with dATP, but ktr was enhanced at higher Ca2+ concentrations, resulting in an extension (not elevation) of the ktr-force relationship. Interestingly, we found that maximal ktr was faster than kCa, and that dATP increased both by a similar amount. Our data suggest the dynamics of Ca2+-mediated thin filament activation limits the rate that force develops in rat cardiac muscle, even at saturating levels of Ca2+.
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