Apoptosis-Inducing Factor Regulates Skeletal Muscle Progenitor Cell Number and Muscle Phenotype

Apoptosis Inducing Factor (AIF) is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal and cardiomyocyte apoptosis induced by oxidative stress. Conversely in vitro, AIF has been demonstrated to have a pro-apoptotic role upon induction of the mitochondrial death pathway, once AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. Given that the aif hypomorphic harlequin (Hq) mutant mouse model displays severe sarcopenia, we examined skeletal muscle from the aif hypomorphic mice in more detail. Adult AIF-deficient skeletal myofibers display oxidative stress and a severe form of atrophy, associated with a loss of myonuclei and a fast to slow fiber type switch, both in “slow” muscles such as soleus, as well as in “fast” muscles such as extensor digitorum longus, most likely resulting from an increase of MEF2 activity. This fiber type switch was conserved in regenerated soleus and EDL muscles of Hq mice subjected to cardiotoxin injection. In addition, muscle regeneration in soleus and EDL muscles of Hq mice was severely delayed. Freshly cultured myofibers, soleus and EDL muscle sections from Hq mice displayed a decreased satellite cell pool, which could be rescued by pretreating aif hypomorphic mice with the manganese-salen free radical scavenger EUK-8. Satellite cell activation seems to be abnormally long in Hq primary culture compared to controls. However, AIF deficiency did not affect myoblast cell proliferation and differentiation. Thus, AIF protects skeletal muscles against oxidative stress-induced damage probably by protecting satellite cells against oxidative stress and maintaining skeletal muscle stem cell number and activation

Childhood cognitive skills trajectories and suicide by mid-adulthood:an investigation of the 1958 British Birth Cohort

International audienceBackground : Poor cognitive abilities and low intellectual quotient (IQ) are associated with an increased risk of suicide attempts and suicide mortality. However, knowledge of how this association develops across the life-course is limited. Our study aims to establish whether individuals who died by suicide by mid-adulthood are distinguishable by their child-to-adolescence cognitive trajectories.Methods : Participants were from the 1958 British Birth Cohort and were assessed for academic performance at ages 7, 11, and 16 and intelligence at 11 years. Suicides occurring by September 2012 were identified from linked national death certificates. We compared mean mathematics and reading abilities and rate of change across 7–16 years for individuals who died by suicide v. those still alive, with and without adjustment for potential early-life confounding factors. Analyses were based on 14 505 participants.Results : Fifty-five participants (48 males) had died by suicide by age 54 years. While males who died by suicide did not differ from participants still alive in reading scores at age 7 [effect size (g) = −0.04, p = 0.759], their reading scores had a less steep improvement up to age 16 compared to other participants. Adjustments for early-life confounding factors explained these differences. A similar pattern was observed for mathematics scores. There was no difference between individuals who died by suicide v. participants still alive on intelligence at 11 years.Conclusions : While no differences in tests of academic performance and IQ were observed, individuals who died by suicide had a less steep improvement in reading abilities over time compared to same-age peers

The Pathogenesis and Therapies of Striated Muscle Laminopathies

Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition characterized by early contractures, skeletal muscle weakness, and cardiomyopathy. During the last 20 years, various genetic approaches led to the identification of causal genes of EDMD and related disorders, all encoding nuclear envelope proteins. By their respective localization either at the inner nuclear membrane or the outer nuclear membrane, these proteins interact with each other and establish a connection between the nucleus and the cytoskeleton. Beside this physical link, these proteins are also involved in mechanotransduction, responding to environmental cues, such as increased tension of the cytoskeleton, by the activation or repression of specific sets of genes. This ability of cells to adapt to environmental conditions is altered in EDMD. Increased knowledge on the pathophysiology of EDMD has led to the development of drug or gene therapies that have been tested on mouse models. This review proposed an overview of the functions played by the different proteins involved in EDMD and related disorders and the current therapeutic approaches tested so far

The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic β-cell line

A previously uncharacterized putative ion channel, NALCN (sodium leak channel, non-selective), has been recently shown to be responsible for the tetrodotoxin (TTX)-resistant sodium leak current implicated in the regulation of neuronal excitability. Here, we show that NALCN encodes a current that is activated by M3 muscarinic receptors (M3R) in a pancreatic β-cell line. This current is primarily permeant to sodium ions, independent of intracellular calcium stores and G proteins but dependent on Src activation, and resistant to TTX. The current is recapitulated by co-expression of NALCN and M3R in human embryonic kidney-293 cells and in Xenopus oocytes. We also show that NALCN and M3R belong to the same protein complex, involving the intracellular I–II loop of NALCN and the intracellular i3 loop of M3R. Taken together, our data show the molecular basis of a muscarinic-activated inward sodium current that is independent of G-protein activation, and provide new insights into the properties of NALCN channels

Deciphering the genome structure and paleohistory of _Theobroma cacao_

We sequenced and assembled the genome of _Theobroma cacao_, an economically important tropical fruit tree crop that is the source of chocolate. The assembly corresponds to 76% of the estimated genome size and contains almost all previously described genes, with 82% of them anchored on the 10 _T. cacao_ chromosomes. Analysis of this sequence information highlighted specific expansion of some gene families during evolution, for example flavonoid-related genes. It also provides a major source of candidate genes for _T. cacao_ disease resistance and quality improvement. Based on the inferred paleohistory of the T. cacao genome, we propose an evolutionary scenario whereby the ten _T. cacao_ chromosomes were shaped from an ancestor through eleven chromosome fusions. The _T. cacao_ genome can be considered as a simple living relic of higher plant evolution

A DEMETER-like DNA demethylase protein governs tomato fruit ripening

In plants, genomic DNA methylation which contributes to development and stress responses can be actively removed by DEMETER-like DNA demethylases (DML). Indeed, in Arabidopsis DMLs are important for maternal imprinting and endosperm demethylation, but only few studies demonstrate the developmental roles of active DNA demethylation conclusively in this plant. Here we show a direct cause and effect relationship between active DNA demethylation mainly mediated by the tomato DML, SlDML2, and fruit ripening; an important developmental process unique to plants. RNAi SlDML2 knock-down results in ripening inhibition via hypermethylation and repression of the expression of genes encoding ripening transcription factors and rate-limiting enzymes of key biochemical processes such as carotenoid synthesis. Our data demonstrate that active DNA demethylation is central to the control of ripening in tomat

The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: Implications for developing new model organisms

© 2015 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant Ref:G0900802 to CSJ, LRN, SJ & EJR [www.nc3rs.org.uk]