Lattice spacing and cardiac force-length relationship

University Of Illinois At Chicago, Chicago IL

Investigators

Abstract

DESCRIPTION (the applicant?s description verbatim): The overall objective of this proposal is to provide post-doctoral training in the context of testing the hypothesis that the length dependence of cardiac myofilament Ca2+ activation occurs independently of interfilament lattice spacing (ILS). The first aim is to compare effects of protein kinase A (PKA) phosphorylation on ILS and length dependence of Ca2+ activation in skinned mouse cardiac trabeculae containing either the adult cardiac troponin I (cTnI) isoform or the embryonic, neonatal isoform slow skeletal troponin I (ssTnl). X-ray diffraction, the most accurate method to measure actin-myosin distance, is used to measure ILS at various sarcomere lengths and Ca2+ concentrations prior to and following PKA phosphorylation. The second aim of this proposal is to identify the regions of cTnI that are important determinants of length-dependent Ca2+ sensitivity in cardiac myofilaments. Five different chimeras of TnI are constructed from the various domains of cTnI and ssTnl. These chimeras are then placed into skinned mouse cardiac trabeculae using a reconstitution protocol and pCa-force curves are generated. Our data will provide new insights into our understanding of integrated cardiac function, and will be important in formulating new strategies to fight heart disease and dysfunction.