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1 Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin, USA
2 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA
* To whom correspondence should be addressed. E-mail: stelzer{at}physiology.wisc.edu.
Transgenic mice expressing an allele of cardiac troponin T with a C-terminal truncation (cTnTtrunc) exhibit severe diastolic and mild systolic dysfunction. We tested the hypothesis that contractile dysfunction in myocardium expressing low levels of cTnTtrunc (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 (pCa50) and the rate constant of force redevelopment (ktr) in cTnTtrunc and wild-type (WT) skinned myocardium both in the absence and presence of a strong-binding, non-force-generating derivative of myosin subfragment-1 (NEM-S1). Compared to WT, cTnTtrunc mice exhibited greater pCa50, reduced steepness of the force-pCa relationship (nH) and faster ktr at submaximal [Ca2+], i.e., reduced activation-dependence of ktr. Treatment with NEM-S1 elicited similar increases in pCa50 and similar reductions in nH in WT and cTnTtrunc myocardium, but elicited greater increases in ktr at submaximal activation in cTnTtrunc. Contrary to our initial hypothesis, cTnTtrunc 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+]. While these mechanisms would not be expected to depress systolic function per se in cTnTtrunc hearts, they would account for slowed rates of myocardial relaxation during early diastole.
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