This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat to beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca2+ ions at a longer sarcomere length (SL); this is commonly referred to as myofilament length dependent activation. Over the past decade a unifying hypothesis has gained acceptance stating that myofilament length dependent activation is caused by the reduction in thick to thin filament separation upon an increase in SL which, in turn, is hypothesized to increase the probability of cross-bridge formation. Although earlier experimental data by others supported this theory, we have recently completed a comprehensive series of experiments that show that variation of inter-filament spacing in a relaxed muscle is not sufficient to explain SL dependent myofilament activation. Hence, it is still not known in muscle how the information concerning SL is transduced by the contractile apparatus. Accordingly, the overall goal of our research is to elucidate the molecular mechanism(s) that underlie myofilament length dependent activation, to that end we employ X-ray diffraction to understand the structural interaction of myofilament proteins during stretch and how that might impact force production.
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