Recent clinical studies have revealed a new hypertrophic cardiomyopathy-associated mutation (F87L) in the central region of human cardiac troponin T (TnT). However， despite its implication in several incidences of sudden cardiac death in young and old adults， whether F87L is associated with cardiac contractile dysfunction is unknown. Because the central region of TnT is important for modulating the muscle length-mediated recruitment of new force-bearing cross-bridges (XBs)， we hypothesize that the F87L mutation causes molecular changes that are linked to the length-dependent activation of cardiac myofilaments. Length-dependent activation is important because it contributes significantly to the Frank-Starl... More
Recent clinical studies have revealed a new hypertrophic cardiomyopathy-associated mutation (F87L) in the central region of human cardiac troponin T (TnT). However， despite its implication in several incidences of sudden cardiac death in young and old adults， whether F87L is associated with cardiac contractile dysfunction is unknown. Because the central region of TnT is important for modulating the muscle length-mediated recruitment of new force-bearing cross-bridges (XBs)， we hypothesize that the F87L mutation causes molecular changes that are linked to the length-dependent activation of cardiac myofilaments. Length-dependent activation is important because it contributes significantly to the Frank-Starling mechanism， which enables the heart to vary stroke volume as a function of changes in venous return. We measured steady-state and dynamic contractile parameters in detergent-skinned guinea pig cardiac muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnT) or the guinea pig analogue (TnT) of the human mutation at two different sarcomere lengths (SLs): short (1.9 µm) and long (2.3 µm). TnT increases pCa (-log [Ca] required for half-maximal activation) to a greater extent at short SL than at long SL; for example， pCa increases by 0.25 pCa units at short SL and 0.17 pCa units at long SL. The greater increase in pCa at short SL leads to the abolishment of the SL-dependent increase in myofilament Ca sensitivity (ΔpCa) in TnT fibers， ΔpCa being 0.10 units in TnT fibers but only 0.02 units in TnT fibers. Furthermore， at short SL， TnT attenuates the negative impact of strained XBs on force-bearing XBs and augments the magnitude of muscle length-mediated recruitment of new force-bearing XBs. Our findings suggest that the TnT-mediated effects on cardiac thin filaments may lead to a negative impact on the Frank-Starling mechanism.
