Functional effects of a restrictive-cardiomyopathy-linked cardiac troponin I mutation (R145W) in transgenic mice

• Published in: Journal of molecular biology Vol. 392; no. 5; pp. 1158 - 1167
• Main Authors: Wen, Yuhui, Xu, Yuanyuan, Wang, Yingcai, Pinto, Jose Renato, Potter, James D, Kerrick, W Glenn L
• Format: Journal Article
• Language: English
• Published: England 09-10-2009
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Substitution - genetics; Animals; Cardiomyopathy, Restrictive - genetics; Humans; Mice; Mice, Transgenic; Mutation, Missense; Myocardial Contraction; Myofibrils - physiology; Troponin I - genetics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2009.07.080

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 skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) were explored. Tg-R145W fibers showed an approximately 13-16% increase in maximal Ca(2+)-activated force and ATPase activity compared to hcTnI wild-type transgenic mice. The force-generating cross-bridge turnover rate (g) and the energy cost (ATPase/force) were 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) there would be a large (approximately 53%) increase in force during systole, which may help to partly compensate for diastolic dysfunction. These functional results help to explain the mechanisms by which these mutations give rise to a restrictive phenotype.