ABSTRACT The present study examined the effects of Ca2+ and strongly bound cross-bridges on tension development induced by changes in the concentration of MgADP. Addition of MgADP to the bath increased isometric tension over a wide range of [Ca2+] in skinned fibers from rabbit psoas muscle. Tension-pCa (pCa is -log [Caz+]) relationships and stiffness measurements indicated that MgADP increased mean force per cross-bridge at maximal Ca2+ and increased recruitment of cross-bridges at submaximal Ca2+. Photolysis of caged ADP to cause a 0.5 mM MgADP jump initiated an increase in isometric tension under all conditions examined, even at pCa 6.4 where there was no active tension before ADP release. Tension increased monophasically with an observed rate constant, kApp, which was similar in rate and Ca2+ sensitivity to the rate constant of tension re-development, ktr, measured in the same fibers by a release-re-stretch protocol. The amplitude of the caged ADP tension transient had a bell-shaped dependence on Ca2+, reaching a maximum at intermediate Ca2+ (pCa 6). The role of strong binding cross-bridges in the ADP response was tested by treatment of fibers with a strong binding derivative of myosin subfragment 1 (NEM-Sl). In the presence of NEM-S1, the rate and amplitude of the caged ADP response were no longer sensitive to variations in the level of activator Ca2+. The results are consistent with a model in which ADP-bound cross-bridges cooperatively activate the thin filament regulatory system at submaximal Ce+. This cooperative interaction influences both the magnitude and kinetics of force generation in skeletal muscle.
INTRODUCTION
Regulation of muscle contraction is a relatively complex process that is initiated by binding of Ca2+ to specific low-affinity sites on the thin filament protein troponin (Gordon et al., 2000). A long-standing hypothesis is that Ca2+ relieves steric inhibition of myosin binding to actin, presumably by inducing a change in position of tropomyosin within the thin filament (Haselgrove, 1973; Huxley, 1973; Parry and Squire, 1973). This hypothesis was supported by the observation that in the presence of ATP(-gammaS) fibers exhibit Ca 21 -regulated stiffness but do not develop tension (Dantzig et al., 1988). Also, the extent of binding of myosin subfragment 1 (SI) to myofibrils has been shown to increase in the presence of Ca2+ (Swartz et al., 1990, 1996).
An alternative model of regulation proposes that Ca2+ regulates a kinetic transition in the cross-bridge cycle, e.g., the Pi release step (Chalovich et al., 1981; Chalovich and Eisenberg, 1982; Rosenfeld and Taylor, 1987). This model was proposed on the basis of observations that Ca2+ regulates acto-myosin ATPase activity but does not significantly influence the binding of myosin SI to actin (Chalovich et al., 1981; Chalovich and Eisenberg, 1982; Rosenfeld and Taylor, 1987). As evidence for regulation of kinetic transitions in muscle fibers, the rate of tension redevelopment (k^sub ^tr) following a period of unloaded shortening increased up to 10-fold over the physiological range of Ca2+ (Brenner, 1988; Metzger et al., 1989). Rates of tension development following photolysis of caged Ca2+ (k^sub ^ca) were similarly accelerated as Ca2+ concentration was increased (Ashley et al., 1991; Araujo and Walker, 1994, 1996).
This work was supported by National Institutes of Health grants HL44114 to J.W.W. and HL25861 to R.L.M.
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[Author Affiliation]
Zhe Lu, Darl R. Swartz, Joseph M. Metzger, Richard L. Moss, and Jeffery W. Walker
Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706 USA
[Author Affiliation]
Address reprint requests to Dr. Jeffery W. Walker, University of Wisconsin School of Medicine, Department of Physiology, 1300 University Avenue, Madison, WI 53706. Tel.: 608-262-6941; Fax: 608-265-5512; E-mail: jwalker@physiology.wisc.edu.
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