Effects of MgADP on Length Dependence of Tension Generation in Skinned Rat Cardiac Muscle

Abstract

Abstract-The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 m decreased the muscle width by Ϸ11% and shifted the midpoint of the pCa-tension relationship (pCa 50 ) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca 2ϩ -activated tension and concomitantly diminished the SL-dependent shift of pCa 50 in a concentration-dependent manner. In contrast, pimobendan, a Ca 2ϩ sensitizer, which promotes Ca 2ϩ binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa 50 , suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1.9 m, osmotic compression, produced by 5% wt/vol dextran (molecular weight Ϸ464 000), reduced the muscle width by Ϸ13% and shifted pCa 50 leftward to a similar degree as that observed when increasing SL to 2.3 m. This favors the idea that a decrease in the interfilament lattice spacing is the primary mechanism for SL-dependent tension generation. MgADP (5 mmol/L) markedly attenuated the dextran-induced shift of pCa 50 , and the degree of attenuation was similar to that observed in a study of varying SL. The actomyosin-ADP complex (AM.ADP) induced by exogenous MgADP has been reported to cooperatively promote myosin attachment to the thin filament. We hereby conclude that the increase in the number of force-generating crossbridges on a decrease in the lattice spacing is masked by the cooperative effect of AM.ADP, resulting in depressed SL-dependent tension generation. The full text of this article is available at http://www.circresaha.org. This intrinsic ability of the heart to alter cardiac output forms the basis for the Frank-Starling law of the heart. It is well established that twitch tension and Ca 2ϩ responsiveness in cardiac muscle preparations are enhanced as muscle length (ie, sarcomere length [SL]) is increased within the normal physiological range (SL from Ϸ1.8 to Ϸ2.3 m). 1-5 Although a number of studies have been conducted to account for the SL dependence of tension generation in living myocardium, its mechanism has not been completely elucidated. 6 However, at the myofilament level, there is an increasing amount of evidence suggesting that the SL dependence is primarily due to a change in the interfilament lattice spacing that accompanies the SL change. 7-9 A possible consequence of the decreased lattice spacing is an increase in the probability of myosin attachment to the thin filament, resulting in an increase in the number of force-generating crossbridges. 7,10,11 Ishiwata and Oosawa 12 proposed a model based on the Ca 2ϩ -dependent flexibility of the thin filament, in which they assumed that (1) the muscle volume (ie, the lattice volume) remains constant on a change in SL and that (2) there is a critical distance between the thick and thin filaments for tension generation. This model quantitatively explains both the stretch-induced increas...

Myofilament Calcium Sensitivity in Skinned Rat Cardiac Trabeculae

“…This conclusion differs from previous studies that provided support for the interfilament spacing hypothesis. 7,8,21 In those Figure 6. Relationship between myofilament lattice spacing and myofilament Ca 2ϩ sensitivity in skinned cardiac trabeculae with varying concentrations of dextran (1% to 6%) in the solutions (nϭ7 to 10).…”

“…3 Application of dextran may affect maximum force development. 8,20,21 Accordingly, we directly determined the effect of dextran application on maximum force in a separate group of trabeculae at SLϭ2.20 m (nϭ6). We found that consecutive application of 1%, 3%, and 6% dextran increased maximal force development, on average, by 13.3Ϯ4.0%, 12.2Ϯ4.6%, and 11.9Ϯ5.2%, respectively, compared with that in trabeculae in the absence of dextran (PϽ0.01).…”

Physiological Functions of the Giant Elastic Protein Titin in Mammalian Striated Muscle

“…Indeed, the thin filament regulatory protein troponin is reportedly involved in the regulation of length dependency by modulating the thin filament state [57,58]. Consistent with this view, varying the thin filament activation level by changing the concentration of MgADP [59] or inorganic phosphate (and H + ) [60] revealed that the length dependence is in proportion to the fraction of recruitable (i.e., resting) crossbridges that can potentially produce active force upon attachment to the thin filaments [61,62]. Recently, Terui et al [63] critically tested the idea that length-dependent activation is tuned via on-off switching of the thin filament state in concert with the titin-based regulations.…”

SCH00013, a Novel Ca2+ Sensitizer With Positive Inotropic and No Chronotropic Action in Heart Failure

“…-induced force generation (19). EMD57033 and CGP-48506 decrease the SL dependence (20), suggesting that these Ca 2+ sensitizing drugs attenuate the Frank-Starling mechanism.…”