Genetics of Mechanosensation in the Heart

Mechanosensation (the ultimate conversion of a mechanical stimulus into a biochemical signal) as well as mechanotransduction (transmission of mechanically induced signals) belong to the most fundamental processes in biology. These effects, because of their dynamic nature, are particularly important for the cardiovascular system. Therefore, it is not surprising that defects in cardiac mechanosensation, are associated with various types of cardiomyopathy and heart failure. However, our current knowledge regarding the genetic basis of impaired mechanosensation in the cardiovascular system is beginning to shed light on this subject and is at the centre of this brief review

MLP (muscle LIM protein) as a stress sensor in the heart

Muscle LIM protein (MLP, also known as cysteine rich protein 3 (CSRP3, CRP3)) is a muscle-specific-expressed LIM-only protein. It consists of 194 amino-acids and has been described initially as a factor involved in myogenesis (Arber et al. Cell 79:221–231, 1994). MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393–403, 1997). At this time, this was the first genetically altered animal model to develop this devastating disease. Interestingly, MLP was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674–2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab 88:78–85, 2006; Geier et al. Circulation 107:1390–1395, 2003; Hershberger et al. Clin Transl Sci 1:21–26, 2008; Knöll et al. Cell 111:943–955, 2002; Knöll et al. Circ Res 106:695–704, 2010; Mohapatra et al. Mol Genet Metab 80:207–215, 2003). Although considerable efforts have been undertaken to unravel the underlying molecular mechanisms—how MLP mutations, either in model organisms or in the human setting cause these diseases are still unclear. In contrast, only precise knowledge of the underlying molecular mechanisms will allow the development of novel and innovative therapeutic strategies to combat this otherwise lethal condition. The focus of this review will be on the function of MLP in cardiac mechanosensation and we shall point to possible future directions in MLP research

The Diversification of the LIM Superclass at the Base of the Metazoa Increased Subcellular Complexity and Promoted Multicellular Specialization

Background: Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass. Results: We have identified and characterized all known LIM domain-containing proteins in six metazoans and three nonmetazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineagespecific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study. Conclusion: Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity

Randomized trial of three doses of vitamin D to reduce deficiency in pregnant Mongolian womenResearch in context

Background: In winter in Mongolia, 80% of adults have 25-hydroxyvitamin D (25(OH)D) concentrations <25 nmol/l (<10 ng/ml) and 99% have <50 nmol/l (<20 ng/ml). The vitamin D dose to avert deficiency during pregnancy in this population is unknown. Methods: We conducted a randomized, controlled, double-blind trial of daily 600, 2000, or 4000 IU vitamin D3 for pregnant women in Mongolia (Clinicaltrials.gov #NCT02395081). We examined 25(OH)D concentrations at baseline (12–16 weeks' gestation), 36–40 weeks' gestation and in umbilical cord blood, using enzyme linked fluorescent assay. Sample size was determined to detect 0.4 standard deviation differences in 25(OH)D concentrations with 80% power. Findings: 119 pregnant women were assigned 600 IU, 121 assigned 2000 IU and 120 assigned 4000 IU from February 2015 through December 2016. Eighty-eight percent of participants took ≥80% of assigned supplements. At baseline, 25(OH)D concentrations were similar across arms; overall mean ± standard deviation concentration was 19 ± 22 nmol/l; 91% were < 50 nmol/l. At 36–40 weeks, 25(OH)D concentrations increased to 46 ± 21, 70 ± 23, and 81 ± 29 nmol/l for women assigned 600, 2000, and 4000 IU, respectively (p < 0.0001 across arms; p = 0.002 for 2000 vs. 4000 IU). Mean umbilical cord 25(OH)D concentrations differed by study arm (p < 0.0001 across arms; p < 0.0001 for 2000 vs. 4000 IU) and were proportional to maternal concentrations. There were no adverse events, including hypercalcemia, attributable to vitamin D supplementation. Interpretation: Daily supplementation of 4000 IU during pregnancy is safe and achieved higher maternal and neonatal 25(OH)D concentrations than 2000 IU. Daily 600 IU supplements are insufficient to prevent vitamin D deficiency in Mongolia. Fund: Anonymous foundation and Brigham and Women's Hospital. Keywords: Vitamin D deficiency, Trial, Pregnancy, Dosin