Abstract
The human cardiac troponin I (hcTnI) mutation, R145W, has been associated with restrictive cardiomyopathy. In this study, simultaneous measurements of ATPase activity and force in transgenic skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) were explored. The Tg-R145W fibers showed a ~13 to ~16% increase in the maximal Ca
2+
activated force and ATPase activity compared to hcTnI wild type transgenic mice (Tg-WT). The force generating cross-bridge turnover rate (g) and energy cost (ATPase/force) was the same in all groups of fibers. Also, the Tg-R145W fibers showed a large increase in the Ca
2+
sensitivity of both force development and ATPase. In intact fibers, the mutation caused prolonged force and intracellular [Ca
2+
] transients and increased time to peak force. Analysis of force and Ca
2+
transients showed that there was a 40% increase in peak force in Tg- R145W muscles which was likely due to the increased Ca
2+
transient duration. The above cited results suggest that: 1) there would be an increase in resistance to ventricular filling during diastole resulting from the prolonged force and Ca
2+
transients that would result in a decrease in ventricular filling (diastolic dysfunction); and 2) a large (approximately 53%) increase in force during systole which may help to compensate, in part, for the diastolic dysfunction. These functional results help to explain the mechanisms by which these mutations give rise to the restrictive phenotype.
