Ca2+ activation of myofilaments from transgenic mouse hearts expressing R92Q mutant cardiac troponin T

The functional consequences of the R92Q mutation in cardiac troponin T (cTn T), linked to familial hypertrophic cardiomyopathy in humans, are not well understood. We have studied steady- and pre-steady-state mechanical activit y of detergent-skinned fiber bundles from a transgenic (TG) mouse model in which 67% of the total cTnT in the heart was replaced by the R92Q mutant cT nT. TG fibers were more sensitive to Ca2+ than nontransgenic (NTG) fibers [ negative logarithm of half maximally activating molar Ca2+ (pCa(50)) = 5.84 +/- 0.01 and 6.12 +/- 0.01 for NTG and TG fibers, respectively]. The shift in pCa50 caused by increasing the sarcomere length from 1.9 to 2.3 mum was significantly higher for TG than for NTG fibers (Delta pCa(50) = 0.13 +/- 0.01 and 0.29 +/- 0.02 for NTG and TG fibers, respectively). The relationsh ips between rate of ATP consumption and steady- state isometric tension wer e linear, and the slopes were the same in NTG and TG fibers. Rate of tensio n redevelopment was more sensitive to Ca2+ in TG than in NTG fibers (pCa(50 ) = 5.71 +/- 0.02 and 6.07 +/- 0.02 for NTG and TG fibers, respectively). W e concluded that overall cross-bridge cycling kinetics are not altered by t he R92Q mutation but that altered troponin-tropomyosin interactions could b e responsible for the increase in myofilament Ca2+ sensitivity in TG myofil aments.