Cardiomyopathy mutation (F88L) in troponin T abolishes length dependency of myofilament Ca2+ sensitivity

Abstract

The F88L mutation in cardiac troponin T (TnTF88L) is associated with hypertrophic cardiomyopathy. Reda and Chandra reveal that it abolishes length-mediated increase in myofilament Ca2+ sensitivity and attenuates cooperative mechanisms governing length-dependent activation.

Hypertrophic and Dilated Cardiomyopathy-Associated Troponin T Mutations R130C and ΔK210 Oppositely Affect Length-Dependent Calcium Sensitivity of Force Generation

“…In any case, it is definitive from previous studies that the mechanism does not apply for all HCM-associated mutations in thin filament proteins and that not all mutations increasing calcium sensitivity enhance LDA. The hypertrophic cardiomyopathyassociated mutation F87L in the central region of cTnT enhances calcium sensitivity but attenuates LDA (Reda and Chandra, 2018) and the RCM-associated mutation hcTnI R145W does not affect LDA although it strongly increases calcium sensitivity (Dvornikov et al, 2016). Thus, modifications of different sites in cTn might exert either positive or negative effects on LDA.…”

Developmental increase in β-MHC enhances sarcomere length–dependent activation in the myocardium

“…Previous studies have shown that an increase in SL leads to a decrease in XB detachment rate ( g ; Stelzer and Moss, 2006; Ford and Chandra, 2013; Reda and Chandra, 2018). To determine whether the age-related increase in β-MHC expression altered the SL dependency of g in guinea pig myocardium, we assessed tension cost and c .…”

Mechanistic complexity of contractile dysfunction in hypertrophic cardiomyopathy

“…Other mutations in cTnT have been reported to increase tension-dependent ATP consumption in transgenic mice, as have thick filament protein mutations in animal models and human fHCM (Chandra et al, 2005; He et al, 2007; Ferrantini et al, 2009; Witjas-Paalberends et al, 2014a,b; Wilder et al, 2015; Birch et al, 2016). The results of the Reda and Chandra (2018) study suggest that uncoupling between contractile function and energetics may not be a universal feature of fHCM, though this needs to be further investigated.…”

“…Reda and Chandra (2018) found that the F88L cTnT mutation increased the Ca 2+ sensitivity of force development at both short and long SL, but that the increase was greater at short SL, thus diminishing the SL dependence of contractile activation. There was also some loss of the apparent cooperativity of force generation, as determined from the slope of the force–pCa relationship.…”

“…For example, an engineered mutation in cardiac troponin C (L48Q) also causes a greater increase in the Ca 2+ sensitivity of force generation at short SL than at long SL and therefore reduces the SL dependence of contractile activation (Korte et al, 2012). Interpretation of the results from rapid stretch measurements led Reda and Chandra (2018) to conclude that at least part of the greater increase in Ca 2+ sensitivity at short SL resulted from a reduced impact of negatively strained cross-bridges on positive force–generating cross-bridges, as well as an enhanced cross-bridge to thin filament–cooperative activation mechanism mediated by the F88L mutation. Further analysis suggested that cross-bridge detachment rate and tension cost were not affected by the mutation at either SL.…”