This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our goal is to study the role of titin in modulating structural parameters of striated muscle, and particularly those that may lead to altered actomyosin interaction. We have focused on experiments that take advantage of differential expression of cardiac titin isoforms to provide a mechanism to vary titin-based passive tension. In the heart, small (N2B) and large (N2BA) titin isoforms are expressed in a species-specific and location-specific manner. N2B titin has a shorter extensible region than N2BA titin and, consequently, produces higher passive tension at a given SL, when compared to N2BA titin. In the bovine heart, the expression ratio of N2B titin to N2BA titin is approximately equal in the ventricle, whereas the atrium expresses predominantly N2BA titin, resulting in higher passive tension in the ventricle. We measured the sarcomere length (SL) dependence of activation in skinned cardiac muscles from the bovine left ventricle (BLV), and bovine left atrium (BLA). Passive tension was also varied in each muscle type by manipulating the pre-history of stretch prior to activation. We found that the SL-dependent increases in Ca2+ sensitivity and maximal Ca2+-activated tension were markedly more pronounced when titin-based passive tension was high. Small-angle X-ray diffraction experiments revealed that the SL dependence of reduction of interfilament lattice spacing is greater in BLV than in BLA and that the lattice spacing is coupled with titin-based passive tension. These results support the notion that titin-based passive tension promotes actomyosin interaction by reducing the lattice spacing.
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