Key result
Z06 improves fractional shortening by ~8% in a transgenic mouse model of dilated cardiomyopathy.
Why the study?
Does 4-Hydroxy Duloxetine β-D-Glucuronide (Z06) improve cardiac function in a D230N-Tm transgenic mouse model of dilated cardiomyopathy?
Does 4-Hydroxy Duloxetine β-D-Glucuronide (Z06) improve cardiac function in a D230N-Tm transgenic mouse model of dilated cardiomyopathy?
The small molecule Z06 improves myofibril ATPase activity and in vivo systolic function in a mouse model of familial dilated cardiomyopathy caused by the D230N-Tm mutation.
Familial dilated cardiomyopathy (DCM) is a genetic heart disorder characterized by enlargement of one or both ventricles, rendering the heart unable to pump blood efficiently. Genetic segregation identified a mutation in α-Tropomyosin (Tm) at residue 230 (D230N-Tm) linked to severe, early onset DCM. To meaningfully link genotype to phenotype our group sought to investigate the effects of D230N-Tm on the biophysical structure of the Tm filament. It was shown that D230N-Tm caused a compaction of the cardiac Troponin T (cTnT)–Tm overlap region and a concomitant decrease in flexibility. Given the altered biophysical properties, we screened for molecules that could target these structural changes utilizing a fully atomistic cardiac thin filament model. Computational modeling and biophysical studies identified small molecule 4-Hydroxy Duloxetine β-D-Glucuronide (Z06) which was shown to alleviate compaction of the overlap and restore flexibility of the Tm filament in vitro . We hypothesized that restoring the flexibility of the overlap region in D230N-Tm would improve regulatory and cardiac function in our D230N-Tm transgenic mice . To investigate the effect of Z06 on D230N-Tm myofibrils we performed an NADH-coupled ATPase assay. ATPase activity was measured at saturating calcium (100uM CaCl 2 ) conditions in the presence (250uM) and absence (0uM) of Z06. In the absence of Z06, D230N-Tm exhibited a decrease in ATPase activity (0.065±0.001 umol/min) compared to NTg littermates (0.094±0.005 umol/min). Addition of 250uM Z06, restored D230N-Tm ATPase rates (0.089±0.003 umol/min) to levels comparable to NTg mice. To then assess the ability of Z06 in improving systolic function we administered Z06 to 2-month-old D230N-Tm mice and their NTg littermates. At baseline, D230N-Tm mice exhibited a decrease in percent fractional shortening (%FS) of 22.50±0.563 compared to their NTg littermates (29.90±0.653. After four weeks of treatment we observed an improvement in %FS in D230N-Tm mice to 24.341±0.812 with no significant changes to systolic function in NTg littermates. Future work will investigate the efficacy of Z06 as a late-stage treatment and assess its general applicability in other thin filament mutations, D219N-Tm (HCM) and R173W-cTnT (DCM).
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Vasquez et al. (2025) studied Familial dilated cardiomyopathy (DCM). 4-Hydroxy Duloxetine β-D-Glucuronide (Z06) vs. Absence of Z06 / baseline was evaluated on Percent fractional shortening (%FS). Administration of the small molecule Z06 for four weeks improved percent fractional shortening in a D230N-Tm transgenic mouse model of dilated cardiomyopathy from 22.50% to 24.34%.
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