The Sarcomeric Control of Energy Conversion
Abstract: The Frank-Starling Law, Fenn Effect, and Suga's suggestions of cardiac muscle constant contractile efficiency establish the dependence of cardiac mechanics and energetics on the loading conditions. Consistent with these observations, this review suggests that the sarcomere control of contraction consists of two dominant feedbacks: (1) a cooperativity mechanism (positive feedback), whereby the number of force-generating cross-bridges (XBs) determines the affinity of calcium binding to the troponin regulatory protein; and (2) a mechanical (negative) feedback, whereby the filament shortening velocity affects the rate of XB turnover from the force to the non-force generating conformation. The study explains the roles of these feedbacks in providing the adaptive control of energy consumption by the loading conditions and validates the dependence of the cooperativity mechanism on the number of strong XBs. The cooperativity mechanism regulates XB recruitment. It explains the cardiac force-length calcium relationship, the related Frank-Starling Law of the heart, and the adaptive control of new XB recruitment and the associated adenosine triphosphate (ATP) consumption. The mechanical feedback explains the force-velocity relationship and the constant and high-contractile efficiency. These mechanisms were validated by testing the force responses to large amplitude (100 nm/sarcomere) sarcomere length (SL) oscillations, in intact tetanized trabeculae (utilizing 30 ?M cyclopiazonic). The force responses to large-length oscillations lag behind the imposed oscillations at low extracellular calcium concentration ([Ca2+]0) and slow frequencies (<4 Hz, 25C), yielding counterclockwise hystereses in the force-length plane. The force was higher during shortening than during lengthening. The area within these hystereses corresponds to the external work generated from new XB recruitment during each oscillation, and it is determined by the delay in the force response. Characterization of the delayed response and its dependence on the SL, force, and calcium allows identification of the regulation of XB recruitment. The direct dependence of the phase on force indicates that XB recruitment is determined directly by the force (i.e., the number of strong XBs) and indirectly by SL or calcium. The suggested feedbacks determine cardiac energetics: 1) the constant and high contractile efficiency is an intrinsic property of the single XB, due to the mechanical feedback; and 2) the XBs are the myocyte sensors that modulate XB recruitment in response to length and load changes through the cooperativity mechanism.
frank-starling law fenn effect cardiac mechanics cooperativity cross-bridge excitation-contraction coupling myosin