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Am J Physiol Heart Circ Physiol 280: H705-H713, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 2, H705-H713, February 2001

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

Murali Chandra1, Veronica L. M. Rundell1, Jil C. Tardiff2, Leslie A. Leinwand3, Pieter P. de Tombe1, and R. John Solaro1

1 Department of Physiology and Biophysics and Cardiovascular Sciences Program, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; 2 Department of Medicine, Albert Einstein College of Medicine, The Bronx, New York 10461; and 3 Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309

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 (Delta pCa50 = 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.

skinned fiber bundles; contraction; calcium sensitivity; cross-bridge cycling; rate constant of tension redevelopment


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