Abstract
The intrinsic cellular mechanisms by which length regulates myocardial contraction, the basis of the Frank–Starling relation, are uncertain. The aim of this work was to test the hypothesis that passive force, possibly via titin, participates in the modulation of Ca2+sensitivity of cardiac contractile proteins induced by stretch. Titin degradation by a mild trypsin digestion modulated passive force induced by increasing from 1.9 to 2.3 μ m sarcomere length in skinned rat cardiac cells. Force–pCa curves were established at these two sarcomere lengths after various durations of trypsin application that induced different passive force levels. They allowed us to evaluate myofilament Ca2+sensitivity by the pCa of half-maximal activation (pCa50). In control conditions, stretching cells from 1.9 to 2.3 μ m induced a leftward shift of pCa50(ΔpCa50) of 0.39±0.03 pCa units (mean±SEM, n=8 cells), reflecting an increase in Ca2+sensitivity of the contractile machinery. Passive force measured every 2 min decreased exponentially after the beginning of the trypsin application (t1/2@12 min). The first 30% decrease of passive force did not affect the stretch-induced variation in Ca2+sensitivity. Then, with further decrease in passive force, ΔpCa50decreased. At the lowest passive force investigated 20% of initial passive force, ΔpCa50decreased by approximately 55%. These effects were not accompanied by a significant modification of either maximal activated force at pCa 4.5 solution or pCa50at 1.9 μ m sarcomere length. This indicates that there was no major functional alteration of the contractile machinery during the protocol as also suggested by contractile and regulatory protein electrophoresis on 2.5–12% gradient and 15% SDS–PAGE gels. Thus, besides modulation induced by the reduced lattice spacing during enhanced heart refilling, Ca2+sensitivity of the cardiac contractile machinery may be controlled at least partially by internal passive load, which is known to be largely attributable to titin.
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