title: The adaptive intracellular control of cardiac muscle function.
abstract: This study explores the mechanisms dominating the regulation of the biochemical energy consumption and the mechanical output of the actin-myosin motor units, the crossbridges (Xbs), in the cardiac sarcomere. Our analytical model, which couples Xbs cycling dynamics with the kinetics of the free Ca(2+) binding to troponin-C (Tn-C), includes two feedback mechanisms: (1) a cooperativity mechanism, whereby the amount of force generating Xbs determines the affinity of calcium binding to the regulatory protein and the force-length relationship (FLR); and (2) a mechanical (negative) feedback, whereby the filament shortening velocity affects the rate of Xb turnover from the force- to the nonforce-generating state, allows the analytical solution for the muscle force-velocity relationship (FVR), and the linear relation between energy consumption and the generated mechanical energy. Our experimental and analytical studies of the force response to large-amplitude sarcomere length (SL) oscillations at various frequencies and constant [Ca(2+)] in the isolated tetanized rat trabeculae reveal that the generated force depends on the history of contraction and establishes the validity of these two feedbacks. The cooperativity mechanism generates counterclockwise (CCW) hystereses, where the muscle generates external work; while at higher frequencies the mechanical feedback produces clockwise (CW) hystereses, where the muscle behaves as a damper. The cooperativity provides the adaptive control of the cardiac response to short-term changes in the load by modulating Xb recruitment. The cardiac efficiency, defined as the ratio of the generated mechanical energy (i.e., external work and pseudo-potential energy) to the sarcomere energy consumption, is determined by the mechanical feedback, reflecting an inherent property of the single Xb. The efficiency is thus independent of the number of strong Xbs and is constant and load independent.
authors.affiliation: Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel. amir@bm.technion.ac.il
authors.forename: Amir
authors.initials: A
authors.lastname: Landesberg
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.forename: Samuel
authors.initials: S
authors.lastname: Sideman
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D006321:Heart / Q000502:physiology*; D013816:Thermodynamics