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PROVIDER: PRJNA1169538 | ENA |
REPOSITORIES: ENA
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Project description:Functional dissection of metabolic trait-associated variants in steady state and stimulated human skeletal muscle cells
| PRJNA1187559 | ENA
Project description:Functional dissection of metabolic trait-associated variants in steady state and stimulated human skeletal muscle cells
| PRJNA1169361 | ENA
Project description:Type 2 diabetes (T2D) is a common metabolic disorder characterized by dysregulation of glucose metabolism. Genome-wide association studies have defined hundreds of signals associated with T2D and related metabolic traits, most of which are found in noncoding regions. Given their central role in insulin production and glucose homeostasis, much focus has been devoted to investigating T2D-associated genetic variation in pancreatic islets; however, metabolic disease pathogenesis and risk is distributed across other important metabolic tissues, including the liver, adipose, and skeletal muscle. Here, we used a massively parallel reporter assay (MPRA) to characterize the regulatory activity of T2D-associated variants in human skeletal muscle cells at basal and multiple stimulatory states. We constructed a library of 1,255 oligos spanning 333 metabolic trait-associated variants, half of which were previously characterized using luciferase reporters or in MPRA libraries in any metabolic tissue, and therefore serve as positive controls. We delivered this library to LHCN-M2 human skeletal muscle myocytes in one of four conditions: (1) undifferentiated or differentiated with (2) basal media, (3) media supplemented with the AMP analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to mimic physiological effects of exercise or (4) media containing sodium palmitate which is known to induce insulin resistance.
2025-01-02 | GSE282190 | GEO
Project description:Type 2 diabetes (T2D) is a common metabolic disorder characterized by dysregulation of glucose metabolism. Genome-wide association studies have defined hundreds of signals associated with T2D and related metabolic traits, most of which are found in noncoding regions. Given their central role in insulin production and glucose homeostasis, much focus has been devoted to investigating T2D-associated genetic variation in pancreatic islets; however, metabolic disease pathogenesis and risk is distributed across other important metabolic tissues, including the liver, adipose, and skeletal muscle. Here, we used a massively parallel reporter assay (MPRA) to characterize the regulatory activity of T2D-associated variants in human skeletal muscle cells at basal and multiple stimulatory states. We constructed a library of 1,255 oligos spanning 333 metabolic trait-associated variants, half of which were previously characterized using luciferase reporters or in MPRA libraries in any metabolic tissue, and therefore serve as positive controls. We delivered this library to LHCN-M2 human skeletal muscle myocytes in one of four conditions: (1) undifferentiated or differentiated with (2) basal media, (3) media supplemented with the AMP analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to mimic physiological effects of exercise or (4) media containing sodium palmitate which is known to induce insulin resistance.
2025-01-02 | GSE282052 | GEO
Project description:Friedreich´s Ataxia (FRDA) is a severe neuromuscular disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled in vivo to address open questions on FRDA pathophysiology. We performed a mass spectrometry (MS)-based proteomics analysis in gastrocnemius skeletal muscle biopsies from genetically confirmed FRDA patients (n=5) and controls. Our data corroborate a predominant mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and an adaptative metabolic shift of contractile proteins. The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle -omics as disease state readout in FRDA.
2023-12-04 | PXD044554 | Pride
Project description:The proper coordination of macrophages is essential for skeletal muscle repair. However, the full heterogenity of macrophages responding to injury has yet to be elucidated on the single-cell level. Furthermore, chronic inflammation may shift macrophage heterogeneity at steady-state and affect the generation of heterogeneity necessary for tissue repair. We use scRNA-sequencing to determine the heterogeneity of skeletal muscle macrophages during infection and wound repair (uninfected and infected). We identify multiple transcriptionally distinct macrophage subsets during injury in uninfected mice as well as during infection at steady-state. Interestingly, in response to injury, infected skeletal muscle macrophages fail to generate certain subsets of reparative macrophages in a timely fashion.
2018-10-04 | GSE113111 | GEO
Project description:Exercise induces skeletal muscle adaptation, and the p38 mitogen-activated protein kinase signaling pathway is thought to play an important role in the adaptive processes. We have obtained new evidence that the gamma isoform of p38 is required for exercise-induced metabolic adaptation in skeletal muscle; however, the neuromuscular activity-dependent target genes of p38gamma remain to be defined. We used microarrays to detail the global programme of gene expression underlying the skeletal muscle genetic reprogramming in response to increased contractile activity and identified distinct classes of up-regulated genes during this process that are dependent on the functional activity of the p38gamma isoform. Skeletal muscle-specific p38gamma knockout mice and the wild type littermates are subject to motor nerve stimulation of one of the tibialis anterior muscles followed by microarray analysis of both the stimulated and the contralateral control muscles.
2010-03-03 | E-GEOD-17620 | biostudies-arrayexpress
Project description:Introduction. Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔGATP) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes. Methods. 31P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers. Results. After showing calibrated 31P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO2max (P = 0.001) and the 2) slope of the relationship of GATP with the rate of oxidative phosphorylation (P = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R2 = 0.55, P = 0.001). Conclusions. Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater GATP, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content per se can explain fractional fat oxidation during mild exercise.
2023-06-29 | PXD043032 | Pride
Project description:Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors, and characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority is located in non-coding DNA regions. This suggest that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism and linked to SNPs associated with the development of obesity and T2D.
2020-03-26 | GSE126101 | GEO
Project description:Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors, and characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority is located in non-coding DNA regions. This suggest that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism and linked to SNPs associated with the development of obesity and T2D.
2020-03-26 | GSE126100 | GEO