Muscle Mechanics

 

Muscle contraction powers voluntary movement, heart contraction and gastric motility.  The underlying molecular machinery responsible for muscle contraction also performs critical cellular processes, from cell motility to cell division.

 

Muscle contraction spans multiple size scales.  Molecular interactions cause the relative sliding of two sets of protein filaments.  This sliding causes subcellular, cellular and macroscopic structures to contract.  Over the past hundred years, measurements have been made at each scale, from classical studies of whole muscle to recent single molecule experiments.  Despite this wealth of data, there is no widely accepted theory of muscle contraction suitable for, say, prediction of locomotor strategies or understanding how molecular defects lead to heart disease.  One of my long-term research goals is to use molecular measurements to develop such a theory.

 

Developing this "bottom-up" theory of muscle contraction requires 1) models that accurately describe molecular measurements; 2) methods to efficiently simulate these models; and 3) techniques to bridge size scales.  When employing these techniques, I work in close collaboration with experimentalists to test model predictions, and generate biologically relevant insights.

 

Example

 

 

 

Movie 1. (Click on image, or here to play)  A "mini-ensemble" of 11 myosin molecules (blue) interacts with an actin filament (red) in the laser trap.  The laser trap is used to hold the two beads on either end of the actin filament.  This is a simulation of experiments performed in the Debold lab, and discussed in publications 1, 2 and 6, below.  Not to scale.

Current Publications on Muscle Mechanics

 

1. Jarvis, K., M. A. Woodward, E. P. Debold and S. Walcott, Acidosis affects muscle contraction by slowing the rates myosin attaches to and detaches from actin. Journal of Muscle Research and Cell Motility, In Press.  PDF

 

2. Longyear, T., S. Walcott*, and E. P. Debold*, The molecular basis of thin filament activation: from single molecule to muscle.   Scientific Reports, Volume 7, page 1822. 2017.  PDF

(*EPD and SW contributed equally)

 

3. Walcott, S. Kad, N., Direct measurements of local coupling between myosin molecules are consistent with a model of muscle activation. PLoS Computational Biology, Volume 11, page e1004599. 2015 PDF

 

4. Walcott, S., Docken, S. and Harris, S. P., Effects of cardiac myosin binding protein-C on actin motility are explained with a drag-activation-competition model.  Biophysical Journal (Letter), Volume 108, pages 10-13. 2015 PDF

 

5. Walcott, S., Muscle activation described with a differential equation model for large ensembles of locally coupled molecular motors.  Physical Review E, 90(4):042717, 2014.  PDF

 

6. Debold, E.P.*, Walcott, S.*, Woodward, M. and Turner, M. A., Direct observation of phosphate inhibiting the force generating capacity of a mini ensemble of myosin molecules. Biophysical Journal, Volume 105, pages 2374-2384. 2013. PDF  (*EPD and SW contributed equally)

 

7. Walcott, S., A differential equation model for tropomyosin-induced myosin cooperativity describes myosin-myosin interactions at low calcium. Cellular and Molecular Bioengineering, Volume 6, pages 13-25. 2013. PDF

 

8. Walcott, S., Warshaw, D.M. and Debold, E.P. Mechanical coupling between myosin molecules causes differences between ensemble and single-molecule measurements. Biophysical Journal, Volume 103, pages 501-10. 2012. PDF

 

9. Debold, E. P., Turner, M., Stout, J.C. and Walcott, S. Phosphate enhances myosin-powered actin filament velocity under acidic conditions in a motility assay. American Journal of Physiology, Volume 300, pages R1401-R1408, 2011. PDF

10. Walcott, S., Warshaw, D. M., Modeling smooth muscle myosinÕs two heads: long-lived enzymatic roles and phosphorylation-dependent equilibria. Biophysical Journal, Volume 99, pages 1129-38, 2010. PDF

 

11. Walcott, S., Sun, S. X., Hysteresis in Cross-bridge models of muscle. Physical Chemistry Chemical Physics, Volume 11, pages 4871-81, 2009. PDF

 

12. Walcott, S., Fagnant, P. M., Trybus, K.M., Warshaw, D. M., Smooth muscle heavy meromyosin phosphorylated on one of its two heads supports force and motion. Journal of Biological Chemistry, Volume 284, pages 18244-51, 2009. PDF

 

13. Walcott S. and Herzog, W., Modeling residual force enhancement with generic cross-bridge models. Mathematical Biosciences. Volume 216, pages 172-86, 2008. PDF

Collaborators

 

Ned Debold

Steffen Docken

Samantha Harris

Walter Herzog

Neil Kad

Sean Sun

Kathy Trybus

David Warshaw

Doug Swank

Katy Jarvis