Genetic variants in myostatin and its receptors promote elite athlete status

Background While product of the myostatin gene (MSTN) is an important factor influencing muscle growth, which is well confirmed in nonhuman species, it has not been clearly confirmed whether MSTN expression influences interindividual differences in skeletal muscle mass, affects posttraining changes, or plays a role in the age-related loss of muscle mass and function in humans. Although the inconclusive results are usually explained by ethnic differences and the low frequency of some alleles, it is possible that the role of receptors (ACVR2A and ACVR2B) that affect the biological activity of myostatin is crucial. Therefore, we investigated the sequences of the MSTN, ACVR2A, and ACVR2B genes and determined the interaction between allelic variants and athletic performance and competition level in the Caucasian population. One hundred-two athletes were recruited for the sequencing study, and whole-genome sequencing (WGS) was performed. Second, 330 athletes and 365 controls were included, and real-time PCR was performed.Results The sequence analysis revealed two polymorphisms relatively common in the athlete cohort, and the alternate allele showed overrepresentation in athletes: MSTN rs11333758 and ACVR2A rs3764955. Regarding the polymorphic site MSTN rs11333758, there was a significant overrepresentation of the -/- genotype in all high-elite and mixed-sport high-elite athletes. Carriers of the ACVR2A rs3764955 CC and GG genotypes were more likely to be elite and high-elite athletes. In addition, carriers of the CC genotype were more likely to be in the mixed-sport subelite group. The gene-gene interaction analysis revealed that mixed-sport high elite athletes showed significant underrepresentation of the ACVR2A rs3764955 GC - MSTN rs11333758 AA genotype combination. In the same group, we observed a significant overrepresentation of the ACVR2A rs3764955 GC - MSTN rs11333758 -/- and the ACVR2A rs3764955 CC - MSTN rs11333758 -/- genotype combinations.Conclusions We showed that the specific genotypes of the MSTN rs11333758 and ACVR2A rs3764955, either individually or in gene-gene combination, are significantly associated with athletes' competition level in the Polish population, especially in the mixed-sports athlete group. Thus, although further research is required, these polymorphisms, alone or in combination with other polymorphisms, are among the numerous candidates that could explain individual variations in muscle phenotypes

Transmission Distortion of MCT1 rs1049434 among Polish Elite Athletes

Background: To date, nearly 300 genetic markers were linked to endurance and power/strength traits. The current study aimed to compare genotype distributions and allele frequencies of the common polymorphisms: MCT1 rs1049434, NRF2 rs12594956, MYBPC3 rs1052373 and HFE rs1799945 in Polish elite athletes versus nonathletes. Methods: The study involved 101 male elite Polish athletes and 41 healthy individuals from the Polish population as a control group. SNP data were extracted from whole-genome sequencing (WGS) performed using the following parameters: paired reads of 150 bps, at least 90 Gb of data per sample with 300 M reads and 30x mean coverage. Results: All the analyzed polymorphisms conformed to Hardy-Weinberg equilibrium (HWE) in athletes and the control group, except the MCT1 rs1049434, where allele T was over-represented in the elite trainers' group. No significant between-group differences were found for analyzed polymorphisms. Conclusions: The MCT1 rs1049434 transmission distortion might be characteristic of Polish athletes and the effect of strict inclusion criteria. This result and the lack of statistically significant changes in the frequency of other polymorphisms between the groups might result from the small group size

First-order phase transition vs. spin-state quantum-critical scenarios in strain-tuned epitaxial cobaltite thin films

Pr-containing perovskite cobaltites exhibit unusual valence transitions, coupled to coincident structural, spin-state, and metal-insulator transitions. Heteroepitaxial strain was recently used to control these phenomena in the model (Pr$_{1-y}$Y$_y$)$_{1-x}$Ca$_x$CoO$_{3-\delta}$ system, stabilizing a nonmagnetic insulating phase under compression (with a room-temperature valence/spin-state/metal-insulator transition) and a ferromagnetic metallic phase under tension, thus exposing a potential spin-state quantum critical point. The latter has been proposed in cobaltites and can be probed in this system as a function of a disorder-free variable (strain). We study this here via thickness-dependent strain relaxation in compressive SrLaAlO$_4$(001)/(Pr$_{0.85}$Y$_{0.15}$)$_{0.70}$Ca$_{0.30}$CoO$_{3-\delta}$ epitaxial thin films to quasi-continuously probe structural, electronic, and magnetic behaviors across the nonmagnetic-insulator/ferromagnetic-metal boundary. High-resolution X-ray diffraction, electronic transport, magnetometry, polarized neutron reflectometry, and temperature-dependent magnetic force microscopy provide a detailed picture, including abundant evidence of temperature- and strain-dependent phase coexistence. This indicates a first-order phase transition as opposed to spin-state quantum-critical behavior, which we discuss theoretically via a phenomenological Landau model for coupled spin-state and magnetic phase transitions.Comment: main text + supplementary materia

Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus

Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.Patricia Patricio, Antonio Mateus-Pinheiro, Monica Morais, and Nuno Dinis Alves received fellowships from the Portuguese Foundation for Science and Technology (FCT). Michal Korostynski and Marcin Piechota were funded by the POIG De-Me-Ter 3.1 and NCN 2011/03/D/NZ3/01686 grants. This study was co-funded by the Life and Health Sciences Research Institute (ICVS) and ON. 2-O NOVO NORTE-North Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/ 2013, through the European Regional Development Fund (ERDF) and by the SwitchBox Consortium (Contract FP7-Health-F2-2010-259772 from the European Union). The authors declare no conflict of interest

Global gene expression profile progression in Gaucher disease mouse models

<p>Abstract</p> <p>Background</p> <p>Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.</p> <p>Results</p> <p>To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct <it>Gba1 </it>point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the <it>Gba1 </it>mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the <it>Gba1 </it>mutation.</p> <p>Conclusions</p> <p>Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.</p

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.Funding for collection, genotyping, and analysis of stroke samples was provided by Wellcome Trust Case Control Consortium-2, a functional genomics grant from the Wellcome Trust (DNA-Lacunar), the Stroke Association (DNA-lacunar), the Intramural Research Program of National Institute of Ageing (Massachusetts General Hospital [MGH] and Ischemic Stroke Genetics Study [ISGS]), National Institute of Neurological Disorders and Stroke (Siblings With Ischemic Stroke Study, ISGS, and MGH), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (MGH), Deane Institute for Integrative Study of Atrial Fibrillation and Stroke (MGH), National Health and Medical Research Council (Australian Stroke Genetics Collaborative), and Italian Ministry of Health (Milan). Additional support for sample collection came from the Medical Research Council, National Institute of Health Research Biomedical Research Centre and Acute Vascular Imaging Centre (Oxford), Wellcome Trust and Binks Trust (Edinburgh), and Vascular Dementia Research Foundation (Munich). MT is supported by a project grant from the Stroke Association (TSA 2013/01). HSM is supported by an NIHR Senior Investigator award. HSM and SB are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. VT and RL are supported by grants from FWO Flanders. PR holds NIHR and Wellcome Trust Senior Investigator Awards. PAS is supported by an MRC Fellowship. CML’s research is supported by the National Institute for Health Research Biomedical Research Centre (BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's College London, and the BRC for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226

Genetic Control of a Central Pattern Generator: Rhythmic Oromotor Movement in Mice Is Controlled by a Major Locus near Atp1a2

Fluid licking in mice is a rhythmic behavior that is controlled by a central pattern generator (CPG) located in a complex of brainstem nuclei. C57BL/6J (B6) and DBA/2J (D2) strains differ significantly in water-restricted licking, with a highly heritable difference in rates (h2≥0.62) and a corresponding 20% difference in interlick interval (mean ± SEM = 116.3±1 vs 95.4±1.1 ms). We systematically quantified motor output in these strains, their F1 hybrids, and a set of 64 BXD progeny strains. The mean primary interlick interval (MPI) varied continuously among progeny strains. We detected a significant quantitative trait locus (QTL) for a CPG controlling lick rate on Chr 1 (Lick1), and a suggestive locus on Chr 10 (Lick10). Linkage was verified by testing of B6.D2-1D congenic stock in which a segment of Chr 1 of the D2 strain was introgressed onto the B6 parent. The Lick1 interval on distal Chr 1 contains several strong candidate genes. One of these is a sodium/potassium pump subunit (Atp1a2) with widespread expression in astrocytes, as well as in a restricted population of neurons. Both this subunit and the entire Na+/K+-ATPase molecule have been implicated in rhythmogenesis for respiration and locomotion. Sequence variants in or near Apt1a2 strongly modulate expression of the cognate mRNA in multiple brain regions. This gene region has recently been sequenced exhaustively and we have cataloged over 300 non-coding and synonymous mutations segregating among BXD strains, one or more of which is likely to contribute to differences in central pattern generator tempo

Dissection of a QTL Hotspot on Mouse Distal Chromosome 1 that Modulates Neurobehavioral Phenotypes and Gene Expression

A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21–q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of ∼20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes