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. 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. At the cellular level, sarcomere length (SL) dependent myofilament Ca2+ sensitivity underlies this phenomenon (length dependent activation-LDA). How information concerning SL is transduced by the contractile apparatus of muscle is not known. The overall goal of our research is to elucidate the molecular mechanisms that underlie LDA. Since we have recently found that inter-filament spacing in a relaxed muscle does not underlie LDA our first aim is to test the hypothesis that it is inter-filament spacing attained in an active muscle that underlies LDA. Secondly, we have recently found that troponin, and particularly cardiac troponin-l, plays a pivotal role in LDA. Therefore, in our second aim will determine the role of troponin and cooperative activation in myofilament length dependent activation. We will test the hypothesis that cardiac troponin is sufficient and/or required to impart LDA upon a striated muscle; combined X-ray diffraction and mechanical experiments will be performed using recombinant protein extraction-reconstitution experiments in skinned muscle. Although the Frank-Starling Law of the Heart constitutes a fundamental property of the heart that has been appreciated for well over a century, the molecular mechanisms that underlie this phenomenon are still incompletely understood. Our research plan is aimed to enhance our understanding of this important physiological process that controls cardiac performance on a beat to beat basis.
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