Meeting Abstract

P1.155  Wednesday, Jan. 4  Force enhancement of soleus muscles from mdm mice FUQUA, RD*; MONROY, JA; NISHIKAWA, KC; Northern Arizona University

When muscles are stretched actively, tension increases and settles at a steady state that is well above isometric force. The mechanism underlying this behavior, termed force enhancement, remains poorly understood. In this study, we tested the “winding filament” hypothesis (WFH), which accounts for force enhancement of muscle. The WFH states that the protein titin binds to the thin filaments upon Ca2+ influx, thereby increasing titin-based stiffness. As muscle force increases, titin stiffness continues to increase as it winds on the thin filament with each cross-bridge stroke. During active stretch, the work done in elongating titin is stored as elastic potential energy resulting in force enhancement. We used mice with the mdm mutation, a deletion in the N2A region of titin, to elucidate the role of titin during active stretch. We stretched whole soleus muscles stimulated submaximally in two solutions, Kreb’s and dantrolene, which decreases intracellular calcium. By comparing the force responses in these solutions, we were able to isolate the effects of intracellular Ca2+ on force enhancement. We found that wild-type mice showed a large decrease in force following stretch in dantrolene, suggesting that the observed increase in stiffness upon activation is in fact Ca2+-dependent. In contrast, in both solutions the magnitudes of passive and active forces following stretch did not differ in mdm mutant mice. Similar to our results for elastic recoil, these data suggest (1) that upon activation in wild-type muscles, N2A titin binds to thin filaments, which decreases the length and increases the stiffness of titin; and (2) that N2A binding is absent in mdm mutants. These results are consistent with the “winding filament” hypothesis and may help to elucidate the mechanism for force enhancement with stretch. Supported by NSF IOS-1025806.