Alterations in length-dependent activation (LDA) may constitute a mechanism by which cardiomyopathy mutations lead to deleterious phenotypes and compromised heart function because LDA underlies the molecular basis by which the heart tunes myocardial force production on a beat-to-beat basis (Frank-Starling mechanism). In this study， we investigated the effect of DCM-linked mutation (R173W) in human cardiac troponin T (TnT) on myofilament LDA. R173W mutation is associated with left ventricular dilatation and systolic dysfunction， and is found in multiple families. R173W mutation is in the central region (residues 80-180) of TnT， which is known to be important for myofilament cooperativity and crossbridge (X... More
Alterations in length-dependent activation (LDA) may constitute a mechanism by which cardiomyopathy mutations lead to deleterious phenotypes and compromised heart function because LDA underlies the molecular basis by which the heart tunes myocardial force production on a beat-to-beat basis (Frank-Starling mechanism). In this study， we investigated the effect of DCM-linked mutation (R173W) in human cardiac troponin T (TnT) on myofilament LDA. R173W mutation is associated with left ventricular dilatation and systolic dysfunction， and is found in multiple families. R173W mutation is in the central region (residues 80-180) of TnT， which is known to be important for myofilament cooperativity and crossbridge (XB) recruitment. Steady-state and dynamic contractile parameters were measured in detergent-skinned guinea pig left ventricular muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnT) or mutant TnT (TnT; guinea pig analog of human R173W mutation) at two different sarcomere lengths (SL): short (1.9 μm) and long (2.3 μm). TnT decreased pCa (-log [Ca] required for half-maximal activation) to a greater extent at long than at short SL; for example， pCa decreased by 0.12 pCa units at long SL and by 0.06 pCa units at short SL. Differential changes in pCa at short and long SL attenuated the SL-dependent increase in myofilament Ca sensitivity (ΔpCa) in TnT fibers; ΔpCa was 0.10 units in TnT fibers but only 0.04 units in TnT fibers. Furthermore， TnT blunted the SL-dependent increase in the magnitude of XB recruitment. Our observations suggest that the R173W mutation in human cardiac TnT may impair Frank-Starling mechanism.
