Meeting Abstract
The sliding filament theory fails to explain several characteristics of muscle function, including enhancement of force with stretch and depression of force with shortening. The winding filament hypothesis (WFH) adds to the sliding filament theory by introducing a role for titin in muscle contraction. The WFH predicts that titin is activated upon calcium influx and the N2A region of titin binds to actin. The PEVK region of titin winds upon actin due to rotation of actin by the cross-bridges. In mice, a deletion in the N2A region of the titin gene (the mdm mutation) results in different active and passive muscle properties compared to wild-type mice. The goal of this study was to examine how force depression during shortening changes over many activation levels using muscles from wild-type and mdm mutant mice. Soleus muscles were extracted from wild type and mutant mice, and attached to a force lever, which measured muscle length and force. Isovelocity tests were performed in order to measure the force produced by the muscles at different shortening velocities and activation levels. Muscle shortening ranged between ±10% of optimal length. Three different levels of activation (partial, none and full) were achieved by modulating the frequency and voltage of stimulation. Wild type muscles showed an increase in force depression as activation level increased. The mdm muscles displayed the same level of force depression at all activation levels. These results suggest that the mechanism that links the amount of force depression with the level of activation in wild-type muscles is absent in muscles of mdm mutant mice. Because the mdm muscles have a deletion in the N2A region of titin (the proposed site for calcium-dependent binding of titin to actin), these results provide support for the WFH that titin plays a role in depression of force with shortening.
