Hypertrophic and Dilated Cardiomyopathy-Associated Troponin T Mutations R130C and ΔK210 Oppositely Affect Length-Dependent Calcium Sensitivity of Force Generation

Length-dependent activation of calcium-dependent myocardial force generation provides the basis for the Frank-Starling mechanism. To directly compare the effects of mutations associated with hypertrophic cardiomyopathy and dilated cardiomyopathy, the native troponin complex in skinned trabecular fibers of guinea pigs was exchanged with recombinant heterotrimeric, human, cardiac troponin complexes containing different human cardiac troponin T subunits (hcTnT): hypertrophic cardiomyopathy-associated hcTnT(R130C), dilated cardiomyopathy-associated hcTnT(Delta K210)or the wild type hcTnT (hcTnT(WT)) serving as control. Force-calcium relations of exchanged fibers were explored at short fiber length defined as 110% of slack length (L-0) and long fiber length defined as 125% ofL(0)(1.25L(0)). At short fiber length (1.1L(0)), calcium sensitivity of force generation expressed by -log [Ca2+] required for half-maximum force generation (pCa(50)) was highest for the hypertrophic cardiomyopathy-associated mutation R130C (5.657 +/- 0.019), intermediate for the wild type control (5.580 +/- 0.028) and lowest for the dilated cardiomyopathy-associated mutation Delta K210 (5.325 +/- 0.038). Lengthening fibers from 1.1L(0)to 1.25L(0)increased calcium sensitivity in fibers containing hcTnT(R130C)(delta-pCa(50)= +0.030 +/- 0.010), did not alter calcium sensitivity in the wild type control (delta-pCa(50)= -0.001 +/- 0.010), and decreased calcium sensitivity in fibers containing hcTnT(Delta K210)(delta-pCa(50)= -0.034 +/- 0.013). Length-dependent activation indicated by the delta-pCa(50)was highly significantly (P< 0.001) different between the two mutations. We hypothesize that primary effects of mutations on length-dependent activation contribute to the development of the diverging phenotypes in hypertrophic and dilated cardiomyopathy.