The skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre)frail older adults. Additionally, we examine the effect of resistancetype exercise training on the muscle transcriptome in healthy older subjects and (pre)frail older adults. Baseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Followup samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistancetype exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week. At baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism, and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r=0.73). Our data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistancetype exercise training. Some agerelated changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistancetype exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and reinnervation in ageing muscle.
Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness.
Sex, Specimen part, Subject
View SamplesMany studies have addressed the effects of adult diet on gene expression in Drosophila melanogaster, however, little is known about how developmental diet influences adult gene expression, and how this interacts with adult dietary conditions.
Relating past and present diet to phenotypic and transcriptomic variation in the fruit fly.
Sex, Specimen part
View SamplesBackground: Moderate weight loss can ameliorate adverse health effects associated with obesity, reflected by an improved adipose tissue (AT) gene expression profile. However, the effect of rate of weight loss on the AT transcriptome is unknown.
Adipose tissue gene expression is differentially regulated with different rates of weight loss in overweight and obese humans.
Sex, Specimen part, Treatment, Subject, Time
View SamplesMolecular adaptation of the intestinal mucosa occurs during microbial conventionalization to maintain a balanced immune response. However, the genetic regulation of such adaptation is obscure. Here, combined analysis of germ free and conventionalized mice revealed that the major molecular adaptations were initiated at day 4 of conventionalization with a strong induction of innate immune functions followed by stimulation of adaptive immune functions. We identified central regulatory genes and reconstructed a common regulatory network that appeared to be sufficient to regulate the dynamic adaptation of the intestinal mucosa to the colonizing microbiota. The majority of the genes within this regulatory network play roles in mucosal inflammatory diseases in mouse and human. We propose that the identified central regulatory network may serve as a genetic signature for control of intestinal homeostasis in healthy mice and may help to unravel the genetic basis of pathway dysregulation in human intestinal inflammatory diseases.
Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice.
Sex, Specimen part
View SamplesEarly perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells (PBMCs) towards a high MUFA or SFA challenge between subjects with different cardiovascular disease risk profiles and to identify fatty-acid specific gene-expression pathways.
High fat challenges with different fatty acids affect distinct atherogenic gene expression pathways in immune cells from lean and obese subjects.
Sex, Specimen part, Subject
View SamplesIntroduction: There is increasing evidence that consumption of cocoa products have a beneficial effect on cardio-metabolic health, but the underlying mechanisms remain unclear. Cocoa contains a complex mixture of flavan-3-ols. Epicatechin, a major monomeric flavan-3-ol, is considered to contribute to the cardio-protective effects of cocoa. We investigated effects of pure epicatechin supplementation on whole genome gene expression profiles of circulating immune cells. Methods: In a randomized, double blind, placebo-controlled cross-over trial, 37 (pre)hypertensive (40-80y) subjects received two 4-week interventions; epicatechin (100mg/day) or placebo with a wash-out period of 4-week between both interventions. Whole genome gene expression profiles of peripheral blood mononuclear cells were determined before and after both interventions. Results: After epicatechin supplementation 1180 genes were significantly regulated, of which 234 were also significantly regulated compared to placebo. Epicatechin supplementation up-regulated gene sets involved in transcription/translation and tubulin folding and down-regulated gene sets involved in inflammation. Only a few genes within these regulated gene sets were actually significantly changed upon epicatechin supplementation. Upstream regulators that were shown to be inhibited were classified as cytokine or inflammatory type molecules. Conclusion: Pure epicatechin supplementation modestly reduced gene expression related to inflammation signalling routes in circulating immune cells. These routes are known to play a role in cardiovascular health
Pure flavonoid epicatechin and whole genome gene expression profiles in circulating immune cells in adults with elevated blood pressure: A randomised double-blind, placebo-controlled, crossover trial.
Treatment, Subject
View SamplesAn increasing amount of evidence suggests that the small intestine may play an important role in the development of metabolic diseases, such as obesity and insulin resistance. The small intestine provides the first barrier between diet and the body. As a result, dysregulation of biological processes and secretion of signal molecules from the small intestine may be of importance in the regulation and dysregulation of whole body metabolic homeostasis. Changes in gene expression of genes involved in lipid metabolism, cell cycle and immune response may contribute to the aetiology of diet-induced obesity and insulin resistance. In the current study we present a detailed investigation on the effects a chow diet, low fat diet and high fat diet on gene expression along the proximal-to-distal axis of the murine small intestine. The reported results provide a knowledge base for upcoming studies on the role of the small intestine in the aetiology of diet-induced diseases.
Cross-species comparison of genes related to nutrient sensing mechanisms expressed along the intestine.
Sex, Specimen part
View SamplesDietary fatty acids have myriads of effects on human health and disease. Many of these effects are likely achieved by altering expression of genes. Several transcription factors have been shown to be responsive to fatty acids, including SREBP-1c, NF-kB, RXRs, LXRs, FXR, HNF4, and PPARs. However, the relative importance of these transcription factors in regulation of gene expression by dietary fatty acids remains unclear. Here, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid in combination with gene expression profiling to examine the acute effects of individual dietary fatty acids on hepatic gene expression in mice. The dietary interventions were performed in parallel in wild-type and PPAR-/- mice, enabling the determination of the specific contribution of PPAR. Depending on chain length and degree of saturation, dietary fatty acids caused a statistically significant change in expression of over 400 genes. Surprisingly, the far majority of genes regulated by dietary fatty acids in wild-type mice were unaltered in mice lacking PPAR, indicating PPAR-dependent regulation. We conclude that the effects of dietary fatty acids on hepatic gene expression are almost entirely mediated by PPAR, indicating that PPAR dominates fatty acid-dependent gene regulation in liver.
Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics.
Sex, Specimen part
View SamplesAlmost a quarter of pediatric patients with Acute Lymphoblastic Leukemia (ALL) suffer from relapses. The biological mechanisms underlying therapy response and development of relapses have remained unclear. In an attempt to better understand this phenomenon, we have analyzed 41 matched diagnosis relapse pairs of ALL patients using genomewide expression arrays (82 arrays) on purified leukemic cells. In roughly half of the patients very few differences between diagnosis and relapse samples were found (stable group), suggesting that mostly extra-leukemic factors (e.g., drug distribution, drug metabolism, compliance) contributed to the relapse. Therefore, we focused our further analysis on 20 samples with clear differences in gene expression (skewed group), reasoning that these would allow us to better study the biological mechanisms underlying relapsed ALL. After finding the differences between diagnosis and relapse pairs in this group, we identified four major gene clusters corresponding to several pathways associated with changes in cell cycle, DNA replication, recombination and repair, as well as B cell developmental genes. We also identified cancer genes commonly associated with colon carcinomas and ubiquitination to be upregulated in relapsed ALL. Thus, about half of relapses are due to selection or emergence of a clone with deregulated expression of a genes involved in pathways that regulate B cell signaling, development, cell cycle, cellular division and replication.
Genome-wide expression analysis of paired diagnosis-relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype.
Sex, Specimen part, Disease
View SamplesFibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARalpha challenge demonstrated the dysregulation of PPARalpha signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver.
Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice.
Sex, Age
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