Abstract
The basis of the Frank-Starling mechanism of the heart is the intrinsic ability of cardiac sarcomeres to produce greater active force in response to stretch (i.e., length-dependent activation). We have reported that troponin plays a key role in this phenomenon via on-off switching of the thin filament state, in concert with titin-based passive force (Terui et al., J Gen. Physiol. 131;275-283:2008). In the present study, we systematically investigated the role of thin filament cooperative activation in length-dependent activation using skinned porcine ventricular muscle at sarcomere lengths of 1.9 and 2.3 μm. MgADP (3 mM) increased Ca2+ sensitivity of force and enhanced the speed of contraction, indicating enhanced cooperative activation. MgADP was found to attenuate length-dependent activation, with and without quasi-complete reconstitution of thin filaments with fast skeletal troponin (sTn; from rabbits). Conversely, inorganic phosphate (Pi, 20 mM) decreased Ca2+ sensitivity of force and the speed of contraction, indicating reduced cooperative activation. Pi enhanced length-dependent activation, with and without sTn reconstitution. Qualitatively similar results were obtained with MgADP or Pi in rabbit fast skeletal muscle, with higher Ca2+ sensitivity of force than in cardiac muscle. Linear regression analysis revealed that the speed of contraction, Ca2+ sensitivity of force and length-dependent activation were strongly correlated in both cardiac and skeletal muscle. These results suggest that length-dependent activation is regulated via thin filament cooperative activation, such that the length-dependent increase in the fraction of cross-bridges is less in high cooperative activation states, coupled with a loss of recruitable cross-bridges.
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