Cardiomyopathy mutation (F88L) in troponin T abolishes length dependency of myofilament Ca 2+ sensitivity.

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 _WT ) or the guinea pig analogue (TnT _F88L ) of the human mutation at two different sarcomere lengths (SLs): short (1.9 µm) and long (2.3 µm). TnT _F88L increases pCa ₅₀ (-log [Ca ²⁺ ] _free required for half-maximal activation) to a greater extent at short SL than at long SL; for example, pCa ₅₀ increases by 0.25 pCa units at short SL and 0.17 pCa units at long SL. The greater increase in pCa ₅₀ at short SL leads to the abolishment of the SL-dependent increase in myofilament Ca ²⁺ sensitivity (ΔpCa ₅₀ ) in TnT _F88L fibers, ΔpCa ₅₀ being 0.10 units in TnT _WT fibers but only 0.02 units in TnT _F88L fibers. Furthermore, at short SL, TnT _F88L 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 _F88L -mediated effects on cardiac thin filaments may lead to a negative impact on the Frank-Starling mechanism.
(© 2018 Reda and Chandra.)