Ca2+-sensitizing effects of the mutations at Ile-79  and Arg-92 of troponin T in hypertrophic cardiomyopathy

Several mutations in human cardiac troponin T (TnT) gene have been reported to cause hypertrophic cardiomyopathy (HCM). To explore the effects of the mutations on cardiac muscle contractile function under physiological conditions, human cardiac TnT mutants, Ile79Asn and Arg92Gln, as well as wild type, were expressed in Escherichia coli and exchanged into permeabilized rabbit cardiac muscle fibers, and Ca2+-activated force was determined. The free Ca2+ concentrations required for tension generation were found to be significantly lower in the mutant TnT-exchanged fibers than in the wild-type TnT-exchanged fibers, whereas no significant differences were found in tension-generating capability under maximal activating conditions and in cooperativity. These results suggest that a heightened Ca2+ sensitivity of cardiac muscle contraction is one of the factors to cause HCM associated with these TnT mutations.

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Functional effects of troponin T mutations found in hypertrophic cardiomyopathy on the Ca2+-activated contraction of skinned cardiac muscle fibers

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)47931-6 ◽

2000 ◽

Vol 82 ◽

pp. 116

Author(s):

Sachio Morimoto ◽

Keita Harada ◽

Fumi Takahashi ◽

Reiko Minakami ◽

Iwao Ohtsuki

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Cardiac Muscle ◽

Troponin T ◽

Muscle Fibers ◽

Cardiac Muscle Fibers

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Hypertrophic cardiomyopathy mutation in cardiac troponin T (R95H) attenuates length-dependent activation in guinea pig cardiac muscle fibers

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00369.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. H1180-H1189 ◽

Cited By ~ 6

Author(s):

Alexis V. Mickelson ◽

Murali Chandra

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Guinea Pig ◽

Central Region ◽

Cardiac Troponin ◽

Sarcomere Length ◽

Troponin T ◽

Cardiac Troponin T ◽

Cross Bridge ◽

Cardiac Muscle Fibers ◽

Length Dependent Activation

The central region of cardiac troponin T (TnT) is important for modulating the dynamics of muscle length-mediated cross-bridge recruitment. Therefore, hypertrophic cardiomyopathy mutations in the central region may affect cross-bridge recruitment dynamics to alter myofilament Ca2+ sensitivity and length-dependent activation of cardiac myofilaments. Given the importance of the central region of TnT for cardiac contractile dynamics, we studied if hypertrophic cardiomyopathy-linked mutation (TnTR94H)-induced effects on contractile function would be differently modulated by sarcomere length (SL). Recombinant wild-type TnT (TnTWT) and the guinea pig analog of the human R94H mutation (TnTR95H) were reconstituted into detergent-skinned cardiac muscle fibers from guinea pigs. Steady-state and dynamic contractile measurements were made at short and long SLs (1.9 and 2.3 µm, respectively). Our results demonstrated that TnTR95H increased pCa50 (−log of free Ca2+ concentration) to a greater extent at short SL; TnTR95H increased pCa50 by 0.11 pCa units at short SL and 0.07 pCa units at long SL. The increase in pCa50 associated with an increase in SL from 1.9 to 2.3 µm (ΔpCa50) was attenuated nearly twofold in TnTR95H fibers; ΔpCa50 was 0.09 pCa units for TnTWT fibers but only 0.05 pCa units for TnTR95H fibers. The SL dependency of rate constants of cross-bridge distortion dynamics and tension redevelopment was also blunted by TnTR95H. Collectively, our observations on the SL dependency of pCa50 and rate constants of cross-bridge distortion dynamics and tension redevelopment suggest that mechanisms underlying the length-dependent activation cardiac myofilaments are attenuated by TnTR95H. NEW & NOTEWORTHY Mutant cardiac troponin T (TnTR95H) differently affects myofilament Ca2+ sensitivity at short and long sarcomere length, indicating that mechanisms underlying length-dependent activation are altered by TnTR95H. TnTR95H enhances myofilament Ca2+ sensitivity to a greater extent at short sarcomere length, thus attenuating the length-dependent increase in myofilament Ca2+ sensitivity.

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