CA2-SENSITIZING EFFECTS OF THE MUTATIONS AT ILE-79 AND ARG-92 OF TROPONIN-T IN HYPERTROPHIC CARDIOMYOPATHY()

Several mutations in human cardiac troponin T (TnT) gene have been rep orted to cause hypertrophic cardiomyopathy (HCM). To explore the effec ts of the mutations on cardiac muscle contractile function under physi ological conditions, human cardiac TnT mutants, Ile79Asn and Arg92Gln, as well as wild type, were expressed in Escherichia coli and exchange d into permeabilized rabbit cardiac muscle fibers, and Ca2+-activated force was determined. The free Ca2+ concentrations required for tensio n generation were found to be significantly lower in the mutant TnT-ex changed fibers than in the wild-type TnT-exchanged fibers, whereas no significant differences were found in tension-generating capability un der maximal activating conditions and in cooperativity. These results suggest that a heightened Ca2+ sensitivity of cardiac muscle contracti on is one of the factors to cause HCM associated with these TnT mutati ons.