Biomechanics and Modeling in Mechanobiology

, Volume 18, Issue 4, pp 921–937 | Cite as

Transient active force generation and stress fibre remodelling in cells under cyclic loading

  • Eoin McEvoy
  • Vikram S. Deshpande
  • Patrick McGarryEmail author
Original Paper


The active cytoskeleton is known to play an important mechanistic role in cellular structure, spreading, and contractility. Contractility is actively generated by stress fibres (SF), which continuously remodel in response to physiological dynamic loading conditions. The influence of actin-myosin cross-bridge cycling on SF remodelling under dynamic loading conditions has not previously been uncovered. In this study, a novel SF cross-bridge cycling model is developed to predict transient active force generation in cells subjected to dynamic loading. Rates of formation of cross-bridges within SFs are governed by the chemical potentials of attached and unattached myosin heads. This transient cross-bridge cycling model is coupled with a thermodynamically motivated framework for SF remodelling to analyse the influence of transient force generation on cytoskeletal evolution. A 1D implementation of the model is shown to correctly predict complex patterns of active cell force generation under a range of dynamic loading conditions, as reported in previous experimental studies.


Active cell force generation Dynamic contractility Stress fibre remodelling Cross-bridge cycling Computational cell mechanics 



Funding support was provided by the Irish Research Council (IRC) postgraduate scholarship (GOIPG/2015/2954), the National University of Ireland Galway Hardiman scholarship, and the Science Foundation Ireland (SFI-12/IP/1723). The authors would like to acknowledge the Irish Centre for High-End Computing (ICHEC) for provision of computational facilities and support.


  1. Abercrombie M (1978) Fibroblasts. J Clin Pathol Suppl (R Coll Pathol) 12:1–6CrossRefGoogle Scholar
  2. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) Molecular biology of the cell. Garland Science, New YorkGoogle Scholar
  3. Balestrini JL, Billiar KL (2009) Magnitude and duration of stretch modulate fibroblast remodeling. J Biomech Eng Am Soc Mech Eng 131(5):051005. CrossRefGoogle Scholar
  4. Chung M-W, Tsoutsman T, Semsarian C (2003) Hypertrophic cardiomyopathy: from gene defect to clinical disease. Cell Res 13(1):9–20. CrossRefGoogle Scholar
  5. Curtin NA, Davies RE (1975) Very high tension with very little ATP breakdown by active skeletal muscle. J Mechanochem Cell Motil 3(2):147–154Google Scholar
  6. Deshpande VS, McMeeking RM, Evans AG (2006) A bio-chemo-mechanical model for cell contractility. Proc Natl Acad Sci USA 103(38):14015–14020. CrossRefGoogle Scholar
  7. Deshpande VS, McMeeking RM, Evans AG (2007) A model for the contractility of the cytoskeleton including the effects of stress-fibre formation and dissociation. Proc R Soc A Math Phys Eng Sci 463(2079):787–815. MathSciNetCrossRefzbMATHGoogle Scholar
  8. Dowling EP, McGarry JP (2014) Influence of spreading and contractility on cell detachment. Ann Biomed Eng 42(5):1037–1048. CrossRefGoogle Scholar
  9. Dowling EP, Ronan W, Ofek G, Deshpande VS, McMeeking RM, Athanasiou KA, McGarry JP (2012) The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: a computational and experimental investigation. J R Soc Interface R Soc 9(77):3469–3479. CrossRefGoogle Scholar
  10. Dowling EP, Ronan W, McGarry JP (2013) Computational investigation of in situ chondrocyte deformation and actin cytoskeleton remodelling under physiological loading. Acta Biomater 9(4):5943–5955. CrossRefGoogle Scholar
  11. Foolen J, Deshpande VS, Kanters FMWW, Baaijens FPTT (2012) The influence of matrix integrity on stress-fiber remodeling in 3D. Biomaterials 33(30):7508–7518. CrossRefGoogle Scholar
  12. Greaser ML, Gergely J (1971) Reconstitution of troponin activity from three protein components. J Biol Chem 246(13):4226–4233Google Scholar
  13. Hara F, Fukuda K, Asada S, Matsukawa M, Hamanishi C (2001) Cyclic tensile stretch inhibition of nitric oxide release from osteoblast-like cells is both G protein and actin-dependent. J Orthop Res 19(1):126–131. CrossRefGoogle Scholar
  14. Hill AV (1938) ‘The heat of shortening and the dynamic constants of muscle. Proc R Soc B Biol Sci 126(843):136–195. CrossRefGoogle Scholar
  15. Hill TL (1974) ‘Theoretical formalism for the sliding filament model of contraction of striated muscle part I. Prog Biophys Mol Biol 28:267–340. CrossRefGoogle Scholar
  16. Hunter PJ, McCulloch AD, ter Keurs HEDJ (1998) Modelling the mechanical properties of cardiac muscle. Prog Biophys Mol Biol 69(2–3):289–331. CrossRefGoogle Scholar
  17. Huxley AF (1957) Muscle structure and theories of contraction. Prog Biophys Biophys Chem 7:255–318CrossRefGoogle Scholar
  18. Huxley AF, Simmons RM (1971) Proposed mechanism of force generation in striated muscle. Nature 233(5321):533–538. CrossRefGoogle Scholar
  19. Kaunas R, Hsu, Deguchi (2010) Sarcomeric model of stretch-induced stress fiber reorganization. Cell Health Cytoskelet 3:13. CrossRefGoogle Scholar
  20. Kovács M, Tóth J, Hetényi C, Málnási-Csizmadia A, Sellers JR (2004) Mechanism of blebbistatin inhibition of myosin II. J Biol Chem Am Soc Biochem Mol Biol 279(34):35557–35563. CrossRefGoogle Scholar
  21. Langanger G, Moeremans M, Daneels G, Sobieszek A, De Brabander M, De Mey J (1986) The molecular organization of myosin in stress fibers of cultured cells. J Cell Biol 102(1):200–209. CrossRefGoogle Scholar
  22. Lessey EC, Guilluy C, Burridge K (2012) From mechanical force to RhoA activation. Biochemistry 51(38):7420–7432. CrossRefGoogle Scholar
  23. Lucas SM, Ruff RL, Binder MD (1987) Specific tension measurements in single soleus and medial gastrocnemius muscle fibers of the cat. Exp Neurol 95(1):142–154CrossRefGoogle Scholar
  24. Lymn RW, Taylor EW (1971) Mechanism of adenosine triphosphate hydrolysis by actomyosin. Biochemistry 10(25):4617–4624CrossRefGoogle Scholar
  25. McEvoy E, Deshpande VS, McGarry P (2017) Free energy analysis of cell spreading. J Mech Behav Biomed Mater. CrossRefGoogle Scholar
  26. McGarry JP, Fu J, Yang MT, Chen CS, McMeeking RM, Evans AG, Deshpande VS (2009) Simulation of the contractile response of cells on an array of micro-posts. Philos Trans Ser A Math Phys Eng Sci 367(1902):3477–3497. MathSciNetCrossRefzbMATHGoogle Scholar
  27. McMahon TA (1984) Muscles, reflexes, and locomotion. Princeton University Press, PrincetonGoogle Scholar
  28. Mitrossilis D, Fouchard J, Guiroy A, Desprat N, Rodriguez N, Fabry B, Asnacios A (2009) Single-cell response to stiffness exhibits muscle-like behavior. Proc Natl Acad Sci USA 106(43):18243–18248. CrossRefGoogle Scholar
  29. Nieponice A, Maul TM, Cumer JM, Soletti L, Vorp DA (2007) ‘Mechanical stimulation induces morphological and phenotypic changes in bone marrow-derived progenitor cells within a three-dimensional fibrin matrix. J Biomed Mater Res, Part A 81A(3):523–530. CrossRefGoogle Scholar
  30. Obbink-Huizer C, Oomens CWJ, Loerakker S, Foolen J, Bouten CVC, Baaijens FPT (2014) Computational model predicts cell orientation in response to a range of mechanical stimuli. Biomech Model Mechanobiol 13(1):227–236. CrossRefGoogle Scholar
  31. Offer G, Ranatunga KW (2013) A cross-bridge cycle with two tension-generating steps simulates skeletal muscle mechanics. Biophys J 105(4):928–940. CrossRefGoogle Scholar
  32. Pathak A, McMeeking RM, Evans AG, Deshpande VS (2011) An analysis of the cooperative mechano-sensitive feedback between intracellular signaling, focal adhesion development, and stress fiber contractility. J Appl Mech 78(4):041001. CrossRefGoogle Scholar
  33. Pellegrin S, Mellor H, Barry P, Andrews P, Jester JV (2007) Actin stress fibres. J Cell Sci 120(Pt 20):3491–3499. CrossRefGoogle Scholar
  34. Rastogi K, Puliyakodan MS, Pandey V, Nath S, Elangovan R (2016) Maximum limit to the number of myosin II motors participating in processive sliding of actin. Sci Rep 6(1):32043. CrossRefGoogle Scholar
  35. Reynolds NH, McGarry JP (2015) Single cell active force generation under dynamic loading—part II: active modelling insights. Acta Biomater 27:251–263. CrossRefGoogle Scholar
  36. Reynolds NH, Ronan W, Dowling EP, Owens P, McMeeking RM, McGarry JP (2014) On the role of the actin cytoskeleton and nucleus in the biomechanical response of spread cells. Biomaterials 35(13):4015–4025. CrossRefGoogle Scholar
  37. Shishvan SS, Vigliotti A, Deshpande VS (2018) The homeostatic ensemble for cells. Biomech Model Mechanobiol. CrossRefGoogle Scholar
  38. Smith DA, Geeves MA (1995) Strain-dependent cross-bridge cycle for muscle. Biophys J 69(2):524–537. CrossRefGoogle Scholar
  39. Smith CW, Marston SB (1985) Disassembly and reconstitution of the Ca2+-sensitive thin filaments of vascular smooth muscle. FEBS Lett 184(1):115–119CrossRefGoogle Scholar
  40. Vernerey FJ, Farsad M (2011) A constrained mixture approach to mechano-sensing and force generation in contractile cells. J Mech Behav Biomed Mater 4(8):1683–1699. CrossRefGoogle Scholar
  41. Vigliotti A, Ronan W, Baaijens FPT, Deshpande VS (2015) A thermodynamically motivated model for stress-fiber reorganization. Biomech Model Mechanobiol. CrossRefGoogle Scholar
  42. Weafer PP, Ronan W, Jarvis SP, McGarry JP (2013) Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression. Bull Math Biol 75(8):1284–1303. MathSciNetCrossRefzbMATHGoogle Scholar
  43. Weafer PP, Reynolds NH, Jarvis SP, McGarry JP (2015) Single cell active force generation under dynamic loading—part I: AFM experiments. Acta Biomater 27:236–250. CrossRefGoogle Scholar
  44. Wille JJ, Elson EL, Okamoto RJ (2006) Cellular and matrix mechanics of bioartificial tissues during continuous cyclic stretch. Ann Biomed Eng 34(11):1678–1690. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Discipline of Biomedical EngineeringNational University of Ireland GalwayGalwayIreland
  2. 2.Department of EngineeringUniversity of CambridgeCambridgeUK

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