The Role Of Ctnt Isoform Switching In Modulating Sarcomeric Cardiomyopathies

An oft-noted component of sarcomeric dilated (DCM) and hypertrophic (HCM) cardiomyopathies is that the same primary mutation can exhibit significant phenotypic variability. This lack of a distinct link between genotype and phenotype suggests independent modifiers exist that differentially affect susceptible individuals. The tropomyosin (Tm) mutation Asp230Asn (D230N), exhibits a “bimodal” distribution of severity primarily impacting children. Of note, survivors often recover significant systolic function by adolescence. To explore the molecular mechanism of this recovery (despite the persistence of D230N-Tm) we hypothesized that the age-dependent remodeling is caused by the Tm binding partner, cardiac Troponin T, transitioning from its fetal (cTnT1) to adult (cTnT3) isoform. Divergent cardiac remodeling was observed in D230N+cTnT1 (DTg) mice, where DTg mice exhibited an additively reduced %FS compared to D230N+cTnT3 mice. We investigated these functional changes at a molecular level via differential scanning calorimetry (DSC). cTnT1 alone had little effect on the structure or function of the thin filament (TF) resulting in a slight increase in flexibility of the overlap. However, D230N+cTnT1 filaments exhibited an additive decrease in flexibility of the Tm-overlap. Coupled with this decreased flexibility was a cTnT1-induced additive reduction in the calcium sensitivity of sliding velocity likely due to disrupted flexibility in the overlap. In contrast, the HCM-linked cTnT mutation Arg92Leu (R92L), also proximal to the Tm-overlap, resulted in an elevated %FS. This supra-normal systolic function decreased toward non-transgenic levels in R92L-cTnT1 mice. Given these functional differences, we suspect a “pinning” of the Tm-overlap in the presence of cTnT1 that lends stability when a mutation that perturbs the flexibility of the Tm-overlap is present. These data suggest a potent modifier effect of fetal cTnT, capable of altering disease severity in a mutation specific manner likely via effects at the crucial Tm-overlap.