Meeting Abstract
We developed a “winding filament” hypothesis for muscle contraction that includes a role for titin in active muscle. The hypothesis proposes that N2A titin binds to actin upon Ca2+ influx in skeletal muscle, and PEVK winds on thin filaments during force development because cross-bridges not only translate but also rotate thin filaments. We used a kinematic model based on the winding filament hypothesis to simulate residual force enhancement in mouse soleus and extensor digitorum longus (EDL). In the simulations, N2A binds to thin filaments on Ca2+ activation, cross-bridges produce axial and radial forces according to the F-L relationship, and radial forces wind titin on thin filaments. Model variables are N2A distance (nm) from the Z-line and PEVK contour length. Residual force enhancement increases as N2A moves closer to the Z-line and as PEVK contour length decreases. We optimized N2A distance and PEVK contour length to fit passive tension and residual force enhancement data (R2 = 0.99) from soleus. Residual force enhancement in soleus is consistent with N2A binding, titin winding geometry, and PEVK contour length predicted by the kinematic model. We asked what changes in N2A or PEVK can explain observed differences in residual force enhancement between soleus and EDL. The simulations predict that N2A is 21 nm closer to the Z-line in EDL than in soleus. This corresponds to a deletion of ~4-5 proximal tandem Ig domains. The predicted difference in N2A location between mouse soleus and EDL is consistent with observed exon skipping events in the rat. Results show that the kinematic model of titin winding makes testable predictions about titin structure and function. Supported by NSF IOS-1025806.
