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

Murali Chandra, Veronica L M Rundell, Jil C Tardiff, Leslie A. Leinwand, Pieter P. De Tombe, R. John Solaro

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Abstract

The functional consequences of the R92Q mutation in cardiac troponin T (cTnT), linked to familial hypertrophic cardiomyopathy in humans, are not well understood. We have studied steady- and pre-steady-state mechanical activity 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 cTnT. TG fibers were more sensitive to Ca2+ than nontransgenic (NTG) fibers [negative logarithm of half maximally activating molar Ca2+ (pCa50) = 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 μm was significantly higher for TG than for NTG fibers (ΔpCa50 = 0.13 ± 0.01 and 0.29 ± 0.02 for NTG and TG fibers, respectively). The relationships between rate of ATP consumption and steady-state isometric tension were linear, and the slopes were the same in NTG and TG fibers. Rate of tension redevelopment was more sensitive to Ca2+ in TG than in NTG fibers (pCa50 = 5.71 ± 0.02 and 6.07 ± 0.02 for NTG and TG fibers, respectively). We concluded that overall cross-bridge cycling kinetics are not altered by the R92Q mutation but that altered troponin-tropomyosin interactions could be responsible for the increase in myofilament Ca2+ sensitivity in TG myofilaments.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume280
Issue number2 49-2
Publication statusPublished - Feb 2001
Externally publishedYes

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Keywords

  • Calcium sensitivity
  • Contraction
  • Cross-bridge cycling
  • Rate constant of tension redevelopment
  • Skinned fiber bundles

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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