Myocardial wall stiffening in a mouse model of persistent truncus arteriosus.

BACKGROUND: Genetic and epigenetic programs regulate dramatic structural changes during cardiac morphogenesis. Concurrent biomechanical forces within the heart created by blood flow and pressure in turn drive downstream cellular, molecular and genetic responses. Thus, a genetic-morphogenetic-biomechanical feedback loop is continually operating to regulate heart development. During the evolution of a congenital heart defect, concomitant abnormalities in blood flow, hemodynamics, and patterns of mechanical loading would be predicted to change the output of this feedback loop, impacting not only the ultimate morphology of the defect, but potentially altering tissue-level biomechanical properties of structures that appear structurally normal. AIM: The goal of this study was to determine if abnormal hemodynamics present during outflow tract formation and remodeling in a genetically engineered mouse model of persistent truncus arteriosus (PTA) causes tissue-level biomechanical abnormalities. METHODS: The passive stiffness of surface locations on the left ventricle (LV), right ventricle (RV), and outflow tract (OFT) was measured with a pipette aspiration technique in Fgf8;Isl1Cre conditional mutant embryonic mouse hearts and controls. Control and mutant experimental results were compared by a strain energy metric based on the measured relationship between pressure and aspirated height, and also used as target behavior for finite element models of the ventricles. Model geometry was determined from 3D reconstructions of whole-mount, confocal-imaged hearts. The stress-strain relationship of the model was adjusted to achieve an optimal match between model and experimental behavior. RESULTS AND CONCLUSION: Although the OFT is the most severely affected structure in Fgf8;Isl1Cre hearts, its passive stiffness was the same as in control hearts. In contrast, both the LV and RV showed markedly increased passive stiffness, doubling in LVs and quadrupling in RVs of mutant hearts. These differences are not attributable to differences in ventricular volume, wall thickness, or trabecular density. Excellent agreement was obtained between the model and experimental results. Overall our findings show that hearts developing PTA have early changes in ventricular tissue biomechanics relevant to cardiac function and ongoing development.

MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3.

Conquering obesity has become a major socioeconomic challenge. Here, we show that reduced expression of the miR-25-93-106b cluster, or miR-93 alone, increases fat mass and, subsequently, insulin resistance. Mechanistically, we discovered an intricate interplay between enhanced adipocyte precursor turnover and increased adipogenesis. First, miR-93 controls Tbx3, thereby limiting self-renewal in early adipocyte precursors. Second, miR-93 inhibits the metabolic target Sirt7, which we identified as a major driver of in vivo adipogenesis via induction of differentiation and maturation of early adipocyte precursors. Using mouse parabiosis, obesity in mir-25-93-106b(-/-) mice could be rescued by restoring levels of circulating miRNA and subsequent inhibition of Tbx3 and Sirt7. Downregulation of miR-93 also occurred in obese ob/ob mice, and this phenocopy of mir-25-93-106b(-/-) was partially reversible with injection of miR-93 mimics. Our data establish miR-93 as a negative regulator of adipogenesis and a potential therapeutic option for obesity and the metabolic syndrome.