FUNCTION OF GIANT SARCOMERE MATRIX PROTEINS IN MUSCLE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The increase in Ca2+ sensitivity that occurs when sarcomere length (SL) is increased (LDA), is considered the cellular basis of the Frank-Starling law of the heart. LDA is also influenced by the isoform of titin, a long elastic molecule responsible for much of the passive tension in working hearts, present in a particular muscle. Recent findings show increased LDA in a mouse model in which the N2B spring element of titin has been excised (N2B KO) (Lee et al., 2010). Here we investigated LDA in the presence of 3% Dextran (to restore in vivo lattice spacing in skinned muscles), the effect of PKA phosphorylation on LDA, and structural changes of myofilaments by using low-angle X-ray diffraction. Fiber bundles of skinned papillary muscle from left ventricular of N2B KO and WT mice were used. The passive tension, SLs and X-ray diffraction patterns were collected at various SLs from 1.95 to 2.3¿m. From X-ray diffraction patterns, myofilament lattice spacing (LS; d10) and the position of the myosin head relative to the thin filaments (intensity ratio; I11/I10) were obtained. We also performed mechanical studies to characterize Ca2+ sensitivity and LDA.