Abstract
Myocardial performance is tightly regulated by sarcomere length (SL), which is thought to be due at least in part to concurrent changes in myofilament lattice spacing and the relative proximity (and binding probability) of myosin heads to actin. Furthermore, crossbridge binding enhances Ca2+ binding to troponin (Tn) in cardiac muscle, a unique form of cooperative thin filament activation whose mechanism is currently unknown. Experiments here were designed to test the hypothesis that the properties of Tn are important in determining the SL dependence of force in cardiac muscle. We compared trabeculae exchanged with WT cTn vs. cTn containing a mutant (L48Q) cTnC with enhanced Ca2+ affinity. L48Q cTnC caused a left-shift in the force-pCa relationship at long (2.3 μm) SL as compared to WT cTnC. Interestingly, L48Q cTnC effectively eliminated SL-dependence of the force-pCa relationship, via a much larger left-shift at short SL, while SL dependence of Fmax was unaffected. This suggests that SL-dependence of cardiac force development can be greatly influenced by the properties of native cTn, perhaps by limiting crossbridge binding, and that this effect is likely most important at shorter SL. Furthermore, increasing the Ca2+ binding and/or cTnC-cTnI interaction properties of cTn (such as with L48Q cTnC) can reduce or eliminate this limitation. Ongoing experiments will determine whether TnI phosphorylation can restore SL dependence by decreasing Tn Ca2+ affinity, thereby reducing myosin access to actin binding sites. This will also be tested by exchange with I61Q cTnC-Tn, a mutant with reduced Ca2+ affinity. Overall, these results imply that the cardiac length-force relationship is governed, at least in part, by properties of thin filament regulatory units. Support appreciated from NIH R01 HL 65497 (MR) and T32 HL07828 (FSK).
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