scholarly journals A muscle growth promoting treatment based on the attenuation of activin/myostatin signalling in young mice results in long-term testicular abnormalities

2021 ◽  
pp. dmm.047555
Author(s):  
Danielle Vaughan ◽  
Robert Mitchell ◽  
Oliver Kretz ◽  
David Chambers ◽  
Maciej Lalowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Growth ◽  
Gene Array ◽  
Drug Repurposing ◽  
Skeletal Muscle Atrophy ◽  
Short Term Treatment ◽  
Growth Promoting ◽  
The Impact ◽  
Detrimental Impact

Activin/Myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules which result in augmenting muscle growth. However, these molecules, in particular Activin, play major roles in tissue homeostasis in numerous organs of the mammalian body. We have recently shown that while the attenuation of Activin/Myostatin results in robust muscle growth, it also has detrimental impact on the testis. Here, we aimed to discover the long-term consequences of a brief period of exposure to molecules that promote muscle on the testis.We demonstrate that muscle hypertrophy promoted by a soluble Activin Type IIB ligand trap (sActRIIB) is a short-lived phenomenon. In stark contrast, short term treatment with sActRIIB results in immediate impact on the testis which persists after the sessions of the intervention. Gene array analysis identifies an expansion in aberrant gene expression over time in the testis initiated by a brief exposure to muscle growth promoting molecules. The impact on the testis results in decreased organ size as well as quantitative and qualitative impact on sperm. Finally, we have used a drug-repurposing strategy to exploit the gene expression data to identify a compound N6-methyladenosine, that may protect the testis from the impact of the muscle growth promoting regime. Taken together, this work shows potential long-term harmful effects of strategies aimed at promoting muscle growth by attenuating Activin/Myostatin signalling. Furthermore, we have identified a molecule that could in future be used to overcome the detrimental impact of sActRIIB treatment on the testis.

scholarly journals Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention

2020 ◽  
Vol 30 (2) ◽  
pp. 276-285
Author(s):  
Danielle Vaughan ◽  
Oliver Kretz ◽  
Ali Alqallaf ◽  
Robert Mitchell ◽  
Jennie L. Von der Heide ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Muscle Growth ◽  
Wild Type ◽  
Dystrophin Expression ◽  
Growth Promoting ◽  
The Impact ◽  
Detrimental Impact ◽  
Target Effects

Duchenne Muscular Dystrophy is a devastating disease caused by the absence of a functional rod-shaped cytoplasmic protein called dystrophin. Several avenues are being developed aimed to restore dystrophin expression in boys affected by this X-linked disease. However, its complete cure is likely to need combinational approaches which may include regimes aimed at restoring muscle mass. Augmenting muscle growth through the manipulation of the Myostatin/Activin signalling axis has received much attention. However, we have recently shown that while manipulation of this axis in wild type mice using the sActRIIB ligand trap indeed results in muscle growth, it also had a detrimental impact on the testis. Here we examined the impact of administering a powerful Myostatin/Activin antagonist in two mouse models of Duchenne Muscular Dystrophy. We report that whilst the impact on muscle growth was not always positive, both models showed attenuated testis development. Sperm number, motility and ultrastructure were significantly affected by the sActRIIB treatment. Our report suggests that interventions based on Myostatin/Activin should investigate off-target effects on tissues as well as muscle.

scholarly journals Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention

2020 ◽  
Author(s):  
Danielle Vaughan ◽  
Oliver Kretz ◽  
Ali Alqallaf ◽  
Robert Mitchell ◽  
Jennie L. Von der Heide ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Muscle Growth ◽  
Wild Type ◽  
Dystrophin Expression ◽  
Growth Promoting ◽  
The Impact ◽  
Detrimental Impact ◽  
Target Effects

Duchenne Muscular Dystrophy is a devastating disease caused by the absence of a functional rod-shaped cytoplasmic protein called dystrophin. Several avenues are being developed aimed to restore dystrophin expression in boys affected by this X-linked disease. However, its complete cure is likely to need combinational approaches which may include regimes aimed at restoring muscle mass. Augmenting muscle growth through the manipulation of the Myostatin/Activin signalling axis has received much attention. However, we have recently shown that while manipulation of this axis in wild type mice using the sActRIIB ligand trap indeed results in muscle growth, it also had a detrimental impact on the testis. Here we examined the impact of administering a powerful Myostatin/Activin antagonist in two mouse models of Duchenne Muscular Dystrophy. We report that whilst the impact on muscle growth was not always positive, both models showed attenuated testis development. Sperm number, motility and ultrastructure were significantly affected by the sActRIIB treatment. Our report suggests that interventions based on Myostatin/Activin should investigate off-target effects on tissues as well as muscle.

scholarly journals The Impact of Long‐Term Physical Activity on Age‐Related Changes in Protein and Gene Expression

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Ian R Lanza ◽  
Daniel K Short ◽  
Kevin R Short ◽  
Yan W Asmann ◽  
Sreekumar Raghavakaimal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physical Activity ◽  
Age Related ◽  
The Impact ◽  
Age Related Changes

scholarly journals “Recalling hidden harms”: autistic experiences of childhood applied behavioural analysis (ABA)

2020 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Owen McGill ◽  
Anna Robinson
Keyword(s):  
Online Questionnaire ◽  
Childhood Experiences ◽  
Content Type ◽  
Face To Face ◽  
Behavioural Analysis ◽  
Autistic Identity ◽  
The Impact ◽  
Detrimental Impact ◽  
Future Practice

Purpose This paper aims to investigate the long-term impacts autistic adults experienced from childhood participation in the applied behavioural analysis (ABA). Design/methodology/approach Possible participants were recruited through advertisements on social media and autism and ABA organisations. Possible participants were given the choice between an online or face-to-face interview or an anonymised online questionnaire. Findings Reflections from 10 participants were indicative of a predominantly detrimental impact of ABA. Reflections gave rise to a core theme “recalling hidden harms of childhood experiences of ABA”. Outcomes are discussed in relation to the impact on autistic identity, current research and progressing understanding of the impacts of early intervention from the autistic perspective. Research limitations/implications The practical implications of ABA are discussed alongside recommendations for future practice and research with the involvement of autistic individuals within interventive processes. Originality/value This is the first paper to take an in-depth, qualitative approach to autistic experiences of ABA. The findings themselves are driven to conceptualise and give voice to the core impacts which carried through participants’ exploration and understanding of self.

Replicative Senescence-Associated Gene Expression Changes In Human MSPCs Independent of Genomic Variations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4775-4775
Author(s):  
Katharina Schallmoser ◽  
Christina Bartmann ◽  
Eva Rohde ◽  
Simone Bork ◽  
Christian Guelly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Bone Marrow ◽  
Large Scale ◽  
Replicative Senescence ◽  
Genomic Stability ◽  
The State ◽  
Efficient Treatment ◽  
The Impact

Abstract Abstract 4775 Background: Based on promising experimental studies with mesenchymal stem and progenitor cells (MSPCs) multiple clinical trials have been initiated. In previous studies we have observed genomic stability of MSPCs after efficient short-term expansion in a humanized GMP compliant system with pooled human platelet lysate (pHPL) replacing fetal bovine serum (FBS) as the cell culture supplement (Schallmoser K. and Strunk D., Journal of Visualized Experiments (32) DOI: 10.3791/1523, 2009). Notably, depending on culture protocols, an extensive propagation with highly variable cell culture duration may be necessary to yield enough MSPCs for therapy. The decline in proliferation rates of MSPCs in the course of the different long-term expansion procedures may indicate a propensity for replicative senescence which may hamper long term functionality in vivo. We have therefore initiated a molecular profiling of senescence-associated regulated genes to determine the state of senescence before MSPC transplantation. Methods: Human bone marrow-derived MSPCs were cultured following a highly efficient two-passage protocol (primary culture of unseparated bone marrow and subsequent large scale expansion; Schallmoser K. et al., Tissue Engineering 14:185-196, 2008) compared to conventional serial passaging in three different growth conditions with regularly more then four passages to obtain comparable final cell numbers. Culture media were either supplemented with FBS in different concentrations or pHPL. Gene expression changes were tested by microarray analysis and selected targets were reanalyzed by quantitative real-time PCR. The genomic stability of MSPCs after long-term culture was determined by array comparative genomic hybridization (CGH). Results: Despite high proliferation rate large scale expanded MSPCs showed genomic stability in array CGH. Long-term MSPC growth induced similar gene expression changes in MSPCs irrespective of isolation and expansion conditions. In particular, genes involved in cell differentiation, apoptosis and cell death were up-regulated, whereas genes involved in mitosis and proliferation were down-regulated. Furthermore, overlapping senescence-associated gene expression changes were found in all MSPC preparations. The genomic copy number variations detected in MSPCs of early and late passages in all culture conditions did not coincide with differentially expressed genes. Conclusion: Our data indicate that MSPC expansion can induce gene expression changes independent of isolation and FBS-supplemented as well as FBS-free expansion conditions. A panel of genes will be presented that might offer a practicable approach to assess MSPC quality with regard to the state of replicative senescence in advance of therapeutic application. Determining the impact of senescence acquired during cell expansion on the therapeutic potential of MSCPs for both immune modulation and organ regeneration may help to develop more efficient treatment strategies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparison of Nasal Epithelial Smoking-Induced Gene Expression on Affymetrix Exon 1.0 and Gene 1.0 ST Arrays

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Xiaoling Zhang ◽  
Marc E. Lenburg ◽  
Avrum Spira
Keyword(s):  
Gene Expression ◽  
Gene Array ◽  
Cost Effective ◽  
Exon Array ◽  
Nasal Epithelium ◽  
Gene Level ◽  
Differential Gene ◽  
Never Smokers ◽  
High Degree ◽  
The Impact

We have previously defined the impact of tobacco smoking on nasal epithelium gene expression using Affymetrix Exon 1.0 ST arrays. In this paper, we compared the performance of the Affymetrix GeneChip Human Gene 1.0 ST array with the Human Exon 1.0 ST array for detecting nasal smoking-related gene expression changes. RNA collected from the nasal epithelium of five current smokers and five never smokers was hybridized to both arrays. While the intersample correlation within each array platform was relatively higher in the Gene array than that in the Exon array, the majority of the genes most changed by smoking were tightly correlated between platforms. Although neither array dataset was powered to detect differentially expressed genes (DEGs) at a false discovery rate (FDR)<0.05, we identified more DEGs than expected by chance using the Gene ST array. These findings suggest that while both platforms show a high degree of correlation for detecting smoking-induced differential gene expression changes, the Gene ST array may be a more cost-effective platform in a clinical setting for gene-level genomewide expression profiling and an effective tool for exploring the host response to cigarette smoking and other inhaled toxins.

scholarly journals Persistence of rhombomeric organisation in the postsegmental hindbrain

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2143-2152 ◽  
Author(s):  
R.J. Wingate ◽  
A. Lumsden
Keyword(s):  
Gene Expression ◽  
Radial Glia ◽  
Ventricular Zone ◽  
In Situ Hybridisation ◽  
Proliferating Cells ◽  
Nuclear Organisation ◽  
Transverse Pattern ◽  
Marginal Zones ◽  
The Impact

Rhombomeres are morphological varicosities of the neural tube that are present between embryonic day (E) 1.5 and E5 and are characterised by compartment organisation, segmentally neuronal organisation and spatially restricted patterns of gene expression. After E5, the segmented origins of the hindbrain become indistinct, while the adult hindbrain has an longitudinal columnar nuclear organisation. In order to assess the impact of the early transverse pattern on later longitudinal organisation, we have used orthotopic quail grafts and in situ hybridisation to investigate the long-term fate of rhombomeres in the embryonic chick hindbrain. The uniformity of mixing between quail and chick cells was first verified using short-term aggregation cultures. The dispersal of the progeny of individual rhombomeres (r) was then assessed by the unilateral, isochronic and orthotopic transplantation of either r2, r3, r4, r5 or r6 from quail to chick at embryonic day E2. In addition, orthotopic, partial rhombomere grafts, encompassing an inter-rhombomere boundary and adjacent rhombomere bodies were used to assess cell mixing within rhombomeres. Operated embryos were incubated to either E7 or E10 when chimaeric brains were removed. Quail cells were identified in whole mounts or serial sections using the quail-specific antibody QCPN. Subsequently, radial glia morphology was assessed either by immunohistochemistry or DiI labelling. A series of fixed hindbrains between E6 and E9 were probed for transcripts of Hoxa-2 and Hoxb-1. Fate-mapping reveals that the progeny of individual rhombomeres form stripes of cells running dorsoventrally through the hindbrain. This pattern of dispersal precisely parallels the array of radial glia. Although the postmitotic progeny of adjacent rhombomeres spread to some extent into each others' territory in intermediate and marginal zones, there is little or no mixing between rhombomeres in the ventricular zone, which thus remains compartmentalised long after the rhombomeric morphology disappears. Segmental gene expression within this layer is also maintained after E5. A more detailed analysis of mixing between proliferating cells, using partial rhombomere grafts, reveals that both mixing and growth are non-uniform within the ventricular layer, suggesting, in particular, that longitudinal expansion within this layer is restricted. Together, these observations suggest that rhombomeres do not disappear at E5, as has previously been supposed, rather they persist in the ventricular zone to at least E9, ensuring a continuity in the presumed segmental cues that specify neuroepithelial cells in the hindbrain.

scholarly journals Exploring the Impact of Cerebrovascular Disease and Major Depression on Non-diseased Human Tissue Transcriptomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Chi-Lam Poon ◽  
Cho-Yi Chen
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Major Depression ◽  
Cerebrovascular Disease ◽  
Human Body ◽  
Association Studies ◽  
Complex Diseases ◽  
Functional Enrichment ◽  
The Impact

BackgroundThe development of complex diseases is contributed by the combination of multiple factors and complicated interactions between them. Inflammation has recently been associated with many complex diseases and may cause long-term damage to the human body. In this study, we examined whether two types of complex disease, cerebrovascular disease (CVD) or major depression (MD), systematically altered the transcriptomes of non-diseased human tissues and whether inflammation is linked to identifiable molecular signatures, using post-mortem samples from the Genotype-Tissue Expression (GTEx) project.ResultsFollowing a series of differential expression analyses, dozens to hundreds of differentially expressed genes (DEGs) were identified in multiple tissues between subjects with and without a history of CVD or MD. DEGs from these disease-associated tissues—the visceral adipose, tibial artery, caudate, and spinal cord for CVD; and the hypothalamus, putamen, and spinal cord for MD—were further analyzed for functional enrichment. Many pathways associated with immunological events were enriched in the upregulated DEGs of the CVD-associated tissues, as were the neurological and metabolic pathways in DEGs of the MD-associated tissues. Eight gene-tissue pairs were found to overlap with those prioritized by our transcriptome-wide association studies, indicating a potential genetic effect on gene expression for circulating cytokine phenotypes.ConclusionCerebrovascular disease and major depression cause detectable changes in the gene expression of non-diseased tissues, suggesting that a possible long-term impact of diseases, lifestyles and environmental factors may together contribute to the appearance of “transcriptomic scars” on the human body. Furthermore, inflammation is probably one of the systemic and long-lasting effects of cerebrovascular events.

scholarly journals Lipodystrophy-like features after total body irradiation among survivors of childhood acute leukemia

2019 ◽  
Vol 8 (4) ◽  
pp. 349-359 ◽  
Author(s):  
Sandrine Visentin ◽  
Gérard Michel ◽  
Claire Oudin ◽  
Béatrice Cousin ◽  
Bénédicte Gaborit ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Leukemia ◽  
Total Body Irradiation ◽  
Adipocyte Differentiation ◽  
Liver Fat ◽  
Functional Characteristics ◽  
Total Body ◽  
Childhood Acute Leukemia ◽  
The Impact

Background/objective The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children’s irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors. Design We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n = 12) or not received (n = 12) TBI. Subjects/methods Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture. Results Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P = 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1 (minus 39%, P = 0.01) and CIDEA (minus 36%, P = 0.004) and a clear alteration of pre-adipocyte differentiation. Conclusions These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.

scholarly journals Long-Term Impact of Zinc Oxide Nanoparticles on Differentiation and Cytokine Secretion of Human Adipose-Derived Stromal Cells

Materials ◽  
2019 ◽  
Vol 12 (11) ◽  
pp. 1823 ◽  
Author(s):  
Katrin Radeloff ◽  
Andreas Radeloff ◽  
Mario Ramos Tirado ◽  
Agmal Scherzad ◽  
Rudolf Hagen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zinc Oxide ◽  
Stromal Cells ◽  
Zinc Oxide Nanoparticles ◽  
Caspase 3 ◽  
Cytokine Secretion ◽  
Oxide Nanoparticles ◽  
Zno Nps ◽  
The Impact

Zinc oxide nanoparticles (ZnO-NPs) are widely utilized, for example in manufacturing paints and in the cosmetic industry. In addition, there is raising interest in the application of NPs in stem cell research. However, cytotoxic, genotoxic and pro-inflammatory effects were shown for NPs. The aim of this study was to evaluate the impact of ZnO-NPs on cytokine secretion and differentiation properties of human adipose tissue-derived stromal cells (ASCs). Human ASCs were exposed to the subtoxic concentration of 0.2 µg/mL ZnO-NPs for 24 h. After four weeks of cultivation, adipogenic and osteogenic differentiation procedures were performed. The multi-differentiation potential was confirmed histologically and using polymerase chain reaction (PCR). In addition, the gene expression of IL-6, IL-8, vascular endothelial growth factor (VEGF) and caspase 3 was analyzed. Over the course of four weeks after ZnO-NPs exposure, no significant differences were detected in the gene expression of IL-6, IL-8, VEGF and caspase 3 compared to non-exposed cells. The differentiation was also not affected by the ZnO-NPs. These findings underline the fact, that functionality of ASCs is likely to be unaffected by ZnO-NPs, despite a long-term disposition of NPs in the cells, supposing that the starting concentration was safely in the non-toxic range. This might provide important information for single-use nanomedical applications of ZnO-NPs.

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