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Expression of cardiac troponin T with COOH-terminal truncation accelerates cross-bridge interaction kinetics in mouse myocardium

¹Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706; and ²Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309

Submitted 23 February 2004 ; accepted in final form 25 May 2004

Transgenic mice expressing an allele of cardiac troponin T (cTnT) with a COOH-terminal truncation (cTnT_trunc) exhibit severe diastolic and mild systolic dysfunction. We tested the hypothesis that contractile dysfunction in myocardium expressing low levels of cTnT_trunc (i.e., <5%) is due to slowed cross-bridge kinetics and reduced thin filament activation as a consequence of reduced cross-bridge binding. We measured the Ca²⁺ sensitivity of force development [pCa for half-maximal tension generation (pCa₅₀)] and the rate constant of force redevelopment (k_tr) in cTnT_trunc and wild-type (WT) skinned myocardium both in the absence and in the presence of a strong-binding, non-force-generating derivative of myosin subfragment-1 (NEM-S1). Compared with WT mice, cTnT_trunc mice exhibited greater pCa₅₀, reduced steepness of the force-pCa relationship [Hill coefficient (n_H)], and faster k_tr at submaximal Ca²⁺ concentration ([Ca²⁺]), i.e., reduced activation dependence of k_tr. Treatment with NEM-S1 elicited similar increases in pCa₅₀ and similar reductions in n_H in WT and cTnT_trunc myocardium but elicited greater increases in k_tr at submaximal activation in cTnT_trunc myocardium. Contrary to our initial hypothesis, cTnT_trunc appears to enhance thin filament activation in myocardium, which is manifested as significant increases in Ca²⁺-activated force and the rate of cross-bridge attachment at submaximal [Ca²⁺]. Although these mechanisms would not be expected to depress systolic function per se in cTnT_trunc hearts, they would account for slowed rates of myocardial relaxation during early diastole.

calcium ion sensitivity of force; kinetics of actin-myosin interaction; skinned myocardium

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