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Influence of the thin filament calcium activation on muscle force production and rate of contraction in cardiac muscle

Norman, Catalina

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2007, Doctor of Philosophy, Ohio State University, Biophysics.

Cardiac muscle contraction is initiated by Ca2+ binding to troponin C (TnC), which triggers conformational changes on the thin filament, allowing the myosin heads (or crossbridges) to attach to actin and the thick filaments to slide along the thin filaments. This study investigated the influence of the thin filament Ca2+ binding affinity on modulating the rate of contraction at various levels of Ca2+ activation in rat skinned cardiac trabeculae at 15°C. The rate of contraction was assessed as the rate of force (tension) redevelopment, or ktr.

Our novel approach was to directly change the level of thin filament Ca2+ activation by incorporating into trabeculae cardiac TnC mutants with various Ca2+ binding affinities. The TnC mutants V44QTnCF27W and F20QTnCF27W, when reconstituted into trabeculae, increased and decreased, respectively, the Ca2+ sensitivity of force production, both in conditions of normal or accelerated crossbridge cycling induced by the presence of added inorganic phosphate (Pi). The rates of contraction at submaximal levels of Ca2+ activation were increased or decreased, respectively, when the muscle was sensitized or desensitized to Ca2+, but the rates of contraction at saturating Ca2+ activation were similar. When crossbridges cycle faster in the presence of Pi, enhancing or reducing the thin filament Ca2+ activation can still increase or decrease the rate of contraction at submaximal levels of force production, but the rates of contraction at maximal levels of Ca2+ activation were similar for trabeculae reconstituted with TnC mutants. This study indicates that the rate of cardiac muscle contraction is modulated, at submaximal levels of Ca2+ activation, by the Ca2+ binding properties of TnC, and at maximal levels of Ca2+ activation, by the kinetics of crossbridge cycling. These results have physiological relevance and possible clinical applications considering that, on a beat-to-beat basis, the heart contracts at submaximum Ca2+ activation. In heart failure, Ca2+ sensitizing TnC mutants would increase the rate of contraction and improve contractility, whereas in hypertrophic cardiomyopathy, Ca2+ desensitizing TnC mutants would correct for the cardiac sensitization and/or the hypercontractile state.

Jack Rall (Advisor)
197 p.

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Citations

  • Norman, C. (2007). Influence of the thin filament calcium activation on muscle force production and rate of contraction in cardiac muscle [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1178751966

    APA Style (7th edition)

  • Norman, Catalina. Influence of the thin filament calcium activation on muscle force production and rate of contraction in cardiac muscle. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1178751966.

    MLA Style (8th edition)

  • Norman, Catalina. "Influence of the thin filament calcium activation on muscle force production and rate of contraction in cardiac muscle." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1178751966

    Chicago Manual of Style (17th edition)