Deletion of Sphingosine 1-Phosphate receptor 1 in cardiomyocytes during development leads to abnormal ventricular conduction and fibrosis.

Sphingosine 1-Phosphate receptor 1 (S1P1 , encoded by S1pr1) is a G protein-coupled receptor that signals in multiple cell types including endothelial cells and cardiomyocytes. Cardiomyocyte-specific deletion of S1pr1 during mouse development leads to ventricular noncompaction, with 44% of mutant mice surviving to adulthood. Adult survivors of embryonic cardiomyocyte S1pr1 deletion showed cardiac hypertrabeculation consistent with ventricular noncompaction. Surprisingly, systolic function in mutant mice was preserved through at least 1 year of age. Cardiac conduction was abnormal in cardiomyocyte S1pr1 mutant mice, with prolonged QRS intervals in mutants as compared with littermate control mice. Immunostaining of hearts from S1pr1 mutant embryos displayed a zone of intermediate Connexin 40 (Cx40) expression in the trabecular myocardium. However, we observed no significant differences in Cx40 and Connexin 43 immunostaining in hearts from adult survivors of embryonic cardiomyocyte S1pr1 deletion, which suggests normalized development of the ventricular conduction system in mutant mice. By contrast, the adult survivors of embryonic cardiomyocyte S1pr1 deletion showed increased cardiac fibrosis as compared with littermate controls. These results demonstrate that ventricular hypertrabeculation caused by embryonic deletion of cardiomyocyte S1pr1 correlates with cardiac fibrosis, which contributes to abnormal ventricular conduction. These results also reveal conduction abnormalities in the setting of hypertrabeculation with normal systolic function, which may be of clinical relevance in humans with ventricular hypertrabeculation.

Three-dimensional trajectories affect the epaxial muscle activity of arboreal snakes crossing gaps.

The need for long-axis support is widespread among non-aquatic vertebrates and may be particularly acute for arboreal snakes when many vertebrae span sizable gaps between branches with diverse orientations. Hence, we used brown tree snakes (Boiga irregularis) bridging gaps to test how three-dimensional trajectories affected muscle activity and whether these motor patterns differed from those for the locomotion of terrestrial snakes and movements of other vertebrates. We used five trajectories: pitch angles of 90, 0 and -90 deg (downward) when yaw=0 deg, and 90 deg yaw angles to the left and right when pitch=0 deg. We recorded movement and electromyograms from the three largest epaxial muscles, which from dorsal to ventral are the semispinalis-spinalis (SSP), longissimus dorsi (LD) and iliocostalis (IL). Overall, the SSP had extensive bilateral activity, which resembled the motor pattern during the dorsiflexion of sidewinding snakes. Unlike any previously described terrestrial snake locomotion, bilateral activity of the LD and IL was also common during gap bridging. The largest amounts of muscle activity usually occurred for horizontal gaps, and muscle activity decreased markedly as soon as the snake's head touched the far edge of the gap. Snakes had the least amount of muscle activity for pitch=-90 deg. While turning sideways, muscles on the convex side had less activity when turning compared with the concave side. Hence, the orientation relative to gravity profoundly affected muscle activity during gap bridging, and these complex three-dimensional movements involved several previously undescribed variants of axial motor pattern.