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Abstract P1062: Regional Differences In Sarcomeric Glycogen Synthase Kinase 3β Maintain Normal Chamber Level Function


 The structure of the left ventricle is spatially and temporally heterogeneous. The heart’s electrical system helps synchronize these events, but mechanical events play an important role as well. However, experimental evidence of the regional mechanical processes that underpin a “normal contraction” remain largely unknown. Despite the differences in deformation between the anterior and posterior walls, sarcomere lengths during filling and ejection are the same in these regions. One explanation for this disconnect is the myocyte’s force production is different despite similar sarcomere lengths, a relationship known as Length Dependent Activation (LDA). Indeed, a modeling study suggested LDA is a critical regulator of mechanical synchrony in the left ventricle. We recently found the serine/threonine kinase GSK-3β localizes to the z-disc and can modulate LDA, and thus hypothesized it may play a role in maintaining normal cardiac synchrony. We used inducible cardiomyocyte specific GSK-3β KO mice and GSK-3βfl/fl/Cre- littermate Con treated with tamoxifen in which GSK-3β was KO for three weeks. We assessed regional differences in GSK-3β protein levels and found that Con mice had substantial regional heterogeneity: 50% more cytosolic GSK-3β in the posterior wall compared to the anterior wall; however, the myofilament-bound GSK-3β was the opposite, with 50%
 less
 GSK-3β in the posterior wall. This regional heterogeneity was lost in KO mice, in which protein levels were homogenously low. There were no differences detected by m-mode echo between Control and KO mice. However, strain analysis revealed a significant interaction (p=0.037) between genotype and region (Anterior vs. Posterior), in which regional differences in Systolic Strain Rate were ablated in the knockout. These data suggest that the regional differences in GSK-3β sarcomeric levels were important for maintaining regional functional heterogeneity. We further observed that sarcomeric GSK-3β levels (but not cytosolic) decreased in a mouse myocardial infarction model, which these findings suggest could worsen mechanical dyssynchrony post-infarct. Perhaps a possible therapy for mechanical dyssynchrony could involve regional restoration of sarcomeric GSK-3β levels to restore synchrony.
