Advertisement

Tuning Cooperativity of Calcium Activation in Cardiac Muscle

  • Momcilo Prodanovic
  • Boban Stojanovic
  • Mladen Maric
  • Danica Prodanovic
  • Srboljub M. MijailovichEmail author
Conference paper
  • 29 Downloads
Part of the Learning and Analytics in Intelligent Systems book series (LAIS, volume 11)

Abstract

Early phase diastole and diastolic performance (filling) via resting ventricular wall tension can be affected by abnormalities in relaxation. This is one of the rarely studied effects of mutations in cardiac muscle sarcomere proteins, which are usually assessed using the force-pCa relations of demembranated muscle or transient twitch contractions in intact muscles. The characteristics of calcium sensitivity (pCa50) and cooperativity (Hill coefficient, nH) may be obtained from force-pCa relations. Using MUSICO simulations, tightly coupled with the experiments, we were able to adjust calcium sensitivity and cooperativity to closely match experimental values by testing the contributions of three mechanisms to contraction and relaxation kinetics: (1) Tm azimuthal movement as a continuous flexible chain (CFC); (2) variations in calcium affinity of cTn; and (3) inclusion of a super-relaxed myosin state (SRX) to reduce the number of myosins that can rebind during relaxation and modulate cooperativity between bound myosin and the CFC.

Simulations provided force-pCa relations where Ca2+ affinity to cTnC was increased or decreased to match the observations in the experiments where native cTnC was replaced with either cTnC L48Q or cTnC I61Q, respectively. Simulations demonstrated that the proposed mechanism, where mutated cTnC changes the dissociation rate of calcium, cannot match experimental pCa50 values for cTnC mutants nor the observed cooperativity (nH). Adjusting the affinity of myosin to actin and the confined persistent length (CPL) of the CFC could account for the apparent loss of cooperativity of thin filament activation for both mutants. However, in WT muscle, the predicted cooperativity was significantly lower than observed. Fine-tuning the calcium dependent transition rate from the SRX, though, allowed a close match to the experimental nH from the force-pCa relations while maintaining CPL values in the physiological range.

Keywords

MUSICO Thin filament regulation Cooperativity Cardiomyopathy cTnC mutations 

Notes

Acknowledgments

This project is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 777204. We are also gratefully acknowledging the help of Prof. Thomas C. Irving with editing the final version of the manuscript.

Note: This article reflects only the author’s view. The European Commission is not responsible for any use that may be made of the information it contains.

References

  1. 1.
    Davis, J., Davis, L.C., Correll, R.N., Makarewich, C.A., Schwanekamp, J.A., Moussavi-Harami, F., et al.: A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 165, 1147–1159 (2016)CrossRefGoogle Scholar
  2. 2.
    Kreutziger, K.L., Piroddi, N., McMichael, J.T., Tesi, C., Poggesi, C., Regnier, M.: Calcium binding kinetics of troponin C strongly modulate cooperative activation and tension kinetics in cardiac muscle. J. Mol. Cell. Cardiol. 50, 165–174 (2011)CrossRefGoogle Scholar
  3. 3.
    Mijailovich, S.M., Stojanovic, B., Nedic, D., Svicevic, M., Geeves, M.A., Irving, T.C., et al.: Nebulin and titin modulate crossbridge cycling and length dependent calcium sensitivity. J. Gen. Physiol. 151, 680–704 (2019)CrossRefGoogle Scholar
  4. 4.
    Mijailovich, S.M., Kayser-Herold, O., Stojanovic, B., Nedic, D., Irving, T.C., Geeves, M.A.: Three-dimensional stochastic model of actin-myosin binding in the sarcomere lattice. J. Gen. Physiol. 148, 459–488 (2016)CrossRefGoogle Scholar
  5. 5.
    Mijailovich, S.M., Prodanovic, M., Vasovic, L., Stojanovic, B., Maric, M., Prodanovic, D., et al.: Modulation of calcium sensitivity and twitch contractions in cardiac muscle with troponin-C mutations: simulations and experiments. Biophys. J. 116, 116a (2019)CrossRefGoogle Scholar
  6. 6.
    Mijailovich, S.M., Nedic, D., Vasovic, L., Stojanovic, B., Powers, J., Davis, J., et al.: Influence of cTn Ca2+ binding properties and cooperative mechanisms on cardiac muscle contractile dynamics. Biophys. J. 114, 500a (2018)CrossRefGoogle Scholar
  7. 7.
    McNamara, J.W., Li, A., Dos Remedios, C.G., Cooke, R.: The role of super-relaxed myosin in skeletal and cardiac muscle. Biophys. Rev. 7, 5–14 (2015)CrossRefGoogle Scholar
  8. 8.
    Irving, M.: Regulation of contraction by the thick filaments in skeletal muscle. Biophys. J. 113, 2579–2594 (2017)CrossRefGoogle Scholar
  9. 9.
    Geeves, M., Griffiths, H., Mijailovich, S., Smith, D.: Cooperative [Ca(2) +]-dependent regulation of the rate of myosin binding to actin: solution data and the tropomyosin chain model. Biophys. J. 100, 2679–2687 (2011)CrossRefGoogle Scholar
  10. 10.
    Mijailovich, S.M., Kayser-Herold, O., Li, X., Griffiths, H., Geeves, M.A.: Cooperative regulation of myosin-S1 binding to actin filaments by a continuous flexible Tm-Tn chain. Eur. Biophys. J. 41, 1015–1032 (2012)CrossRefGoogle Scholar
  11. 11.
    Mijailovich, S.M., Stojanovic, B., Nedic, D., Svicevic, M., Gilbert, R.J., Geeves, M.A., et al.: Modulation of crossbridge cycling kinetics and length dependent calcium sensitivity by titin and nebulin. Biophys. J. 104(2), 310 (2013)CrossRefGoogle Scholar
  12. 12.
    Bathe, K.J.: Finite Element Procedures. Prentice-Hall, Englewood Cliffs (1996)zbMATHGoogle Scholar
  13. 13.
    Bathe, K.J., Mijailovich, S.M.: Finite element analysis of frictional contact problems. J. de Mechanique et Applique 7, 31–47 (1988)zbMATHGoogle Scholar
  14. 14.
    Mijailovich, S.M., Stamenovic, D., Fredberg, J.J.: Toward a kinetic theory of connective tissue micromechanics. J. Appl. Physiol. 74, 665–681 (1993)CrossRefGoogle Scholar
  15. 15.
    Cazorla, O., Wu, Y., Irving, T.C., Granzier, H.: Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes. Circ. Res. 88, 1028–1035 (2001)CrossRefGoogle Scholar
  16. 16.
    Irving, T.C., Konhilas, J., Perry, D., Fischetti, R., de Tombe, P.P.: Myofilament lattice spacing as a function of sarcomere length in isolated rat myocardium. Am. J. Physiol. Heart Circ. Physiol. 279, H2568–H2573 (2000)CrossRefGoogle Scholar
  17. 17.
    Linari, M., Dobbie, I., Reconditi, M., Koubassova, N., Irving, M., Piazzesi, G., et al.: The stiffness of skeletal muscle in isometric contraction and rigor: the fraction of myosin heads bound to actin. Biophys. J. 74, 2459–2473 (1998)CrossRefGoogle Scholar
  18. 18.
    Cazorla, O., Freiburg, A., Helmes, M., Centner, T., McNabb, M., Wu, Y., et al.: Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ. Res. 86, 59–67 (2000)CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Momcilo Prodanovic
    • 1
    • 2
  • Boban Stojanovic
    • 1
    • 3
  • Mladen Maric
    • 1
    • 3
  • Danica Prodanovic
    • 1
    • 3
  • Srboljub M. Mijailovich
    • 4
    Email author
  1. 1.Bioengineering Research and Development Center (BioIRC)KragujevacSerbia
  2. 2.Faculty of EngineeringUniversity of KragujevacKragujevacSerbia
  3. 3.Faculty of ScienceUniversity of KragujevacKragujevacSerbia
  4. 4.Department of BiologyIllinois Institute of TechnologyChicagoUSA

Personalised recommendations