Effect of myostatin inhibition on skeletal muscle gene expression in high fat diet-fed mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130622 | GEO | 2020/05/29
REPOSITORIES: GEO
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Project description:GDF8 (myostatin) is a unique cytokine strongly affecting the skeletal muscle phenotype in human and animals. The aim of the present study was to elucidate the molecular mechanism of myostatin influence on the differentiation of mouse C2C12 myoblasts, using the global-transcriptome analysis with the DNA microarray technique. Treatment with exogenous GDF8 strongly affected the growth and development of C2C12 mouse myoblasts. This was manifested by the inhibition of proliferation and differentiation as well as the impairment of cell fusion. DNA microarray analysis revealed 778 genes regulated by GDF8 in differentiating myoblasts. Ontological analysis revealed their involvement in 17 types of biological processes, 10 types of molecular functions and 68 different signaling pathways. The effect of GDF8 was mainly mediated by the disruption of the cell cycle, calcium and insulin signaling pathways and expression of cytoskeletal and muscle specific proteins.
2014-07-23 | GSE59674 | GEO
Project description:GDF8 (myostatin) is a unique cytokine strongly affecting the skeletal muscle phenotype in human and animals. The aim of the present study was to elucidate the molecular mechanism of myostatin influence on the differentiation of mouse C2C12 myoblasts, using the global-transcriptome analysis with the DNA microarray technique. Treatment with exogenous GDF8 strongly affected the growth and development of C2C12 mouse myoblasts. This was manifested by the inhibition of proliferation and differentiation as well as the impairment of cell fusion. DNA microarray analysis revealed 778 genes regulated by GDF8 in differentiating myoblasts (543 down-regulated and 235 up-regulated). Ontological analysis revealed their involvement in 17 types of biological processes, 10 types of molecular functions and 68 different signaling pathways. The effect of GDF8 was mainly mediated by the disruption of the cell cycle, calcium and insulin signaling pathways and expression of cytoskeletal and muscle specific proteins. The identified key-genes that could play a role as GDF8 targets in differentiating myoblasts are: Mef2, Hgf, Ilb1, Itgb1, Edn1, Ppargc1a. After scanning of hybridized microarrays, quantitation of slide images was performed using Feature Extraction Software (Agilent) using default parameters. The raw data were normalized by Loess normalization method, and then the normalized raw data was exported to GeneSpring GX 11.0.5 (Agilent, Santa Clara, CA). For identification of genes significantly altered in cell compared with the control normal gene set, total detected entities were filtered by flags (present, marginal) to remove very low signal entities and to select reproducible signal values of entities among the replicated experiments, respectively. In statistical analysis, separated for experiment with myoblasts treated with GDF8 ([C2C12]-[GDF8]1-4) was used t-test unpaired (p < 0.05) and fold change over 1.6. Analysis of GO and signaling pathway was carried out using GeneSpring GX 12 (Agilent), KEGG and PANTHER Classification System (http://www.pantherdb.org/). In the analysis of signaling pathways using Panther, a total of 68 cellular pathways were identified.
2014-07-23 | E-GEOD-59674 | biostudies-arrayexpress
Project description:Cannabinoid 1 receptor (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling food intake thorough a central mechanism, and controlling distribution of fuel and utilization in the periphery, particularly in fat and liver. Additionally, inhibition of CB1R improves insulin secretion from pancreatic beta cells and insulin sensitivity in both pancreatic beta cells and hepatocytes. We now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing insulin receptor signaling. Ablation of CB1R in muscle also led to IL-6 secretion and reduced myostatin expression, and enhanced AKT and MAPKs signaling. These changes in myokines induced the expression of myogenic genes, increasing muscle mass and whole-body lean/fat ratio in both obesity and aging, with no change in total body weight. Skm-CB1R-/- mice had increased energy expenditure and their muscle had improved mitochondrial performance, which led to improved physical endurance. These results collectively show that muscle-CB1R is involved in regulating whole-body insulin sensitivity and physical performance.
2020-01-22 | GSE109741 | GEO
Project description:Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called Mss51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, β-oxidation, glycolysis and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51 KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51 KO mice showed an increased oxygen consumption rate compared to WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid β-oxidation were enhanced in skeletal muscle of Mss51 KO mice compared to that of WT mice. We found that mice lacking Mss51 and challenged with a high fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid β-oxidation. These findings demonstrate that Mss51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes.
2019-12-31 | GSE134519 | GEO
Project description:Inhibition of myostatin signaling induces strong skeletal muscle growth making it an attractive target to treat muscle wasting and sarcopenia. However, the biological function of myostatin in the heart is barely understood. We demonstrate that conditional inactivation of myostatin in the adult murine heart leads to cardiac hypertrophy, heart failure and increased lethality. To induce cardiomyocyte specific loss of myostatin a conditionally active Mstn^fl/fl allele was generated by insertion of loxP elements upstream and downstream of exons 1 and 2 of the mouse myostatin gene. The selection cassette was removed in vivo by flp-recombination. To inactivate myostatin, mice were mated to alphaMyHC-MCM mice (Sohal, DS, et al. (2001) Circulation Research 89, 20-25). Cre-recombination was achieved by intraperitoneal administration of Tamoxifen (40 mg/kg) for 5 consecutive days. The respective control alphaMyHC-MCM animals were equally treated.
2014-05-16 | E-MEXP-3744 | biostudies-arrayexpress
Project description:Effect of myostatin inhibition on skeletal muscle gene expression in high fat diet-fed mice
| PRJNA540822 | ENA
Project description:Skeletal muscle, the most abundant body’s tissue, plays vital roles in locomotion and metabolism. Myostatin is a negative regulator of skeletal muscle mass. In addition to increase muscle mass, Myostatin inhibition impacts on muscle contractility and energy metabolism. To decipher the mechanisms of action of the Myostatin inhibitors, we used proteomic and transcriptomic approaches to investigate the changes induced in skeletal muscles of transgenic mice overexpressing Follistatin, a physiological Myostatin inhibitor. Our proteomic workflow included a fractionation step to identify weakly expressed proteins and a comparison of fast versus slow muscles. Functional annotation of altered proteins supports the phenotypic changes induced by Myostatin inhibition, including modifications in energy metabolism, fiber type, insulin and calcium signaling, as well as membrane repair and regeneration. Less than 10% of the differentially expressed proteins were found to be also regulated at the mRNA level but the Biological Process annotation and the KEGG pathways analysis of transcriptomic results showed a great concordance with the proteomic data. Thus, this study describes the most extensive omics analysis of muscle overexpressing Follistatin, providing molecular-level insights to explain the observed muscle phenotypic changes
2017-08-17 | PXD005899 | Pride
Project description:The underlying mechanism of how the atopic lipids in skeletal muscle affect muscle growth remains elusive. Here we chose miniature Bama swine as our model to mimick human obesity and co-associated metabolic disorders by long time diet induction and study how the atopic fat accumulation in skeletal muscle influence muscle function. After 23 months high-fat high-sucrose diet (HFHSD) fed, the model minipig model of obesity accompanied with metabolic disorders like human, and they had increased body weight and extensive lipids deposition in adipose tissues (AT) and non-AT, especially in skeletal muscle. Further more, the mass of skeletal reduced greatly and the small area (0-2000μm2) muscle reduced after diet induced. The average fiber area of Gastroc reduced 25.2%, but no significant changes appeared in the other skeletal muscles. Antioxidant capacity of skeletal muscle also reduced. Microarray profiles showed genes related to fat deposition promotion (Peroxisome proliferator activated receptor γ, CCAAT/enhancer-binding protein α and apolipoprotein E), muscle growth inhibition (myostatin and p21) up regulated, and some other muscle cell differentiation related genes (myoD) down regulated. Meanwhile, adipokines like adiponectin and 11b-hydroxysteroid dehydrogenase type 1 (11βHSD1) which partake in the crosstalk between AT and skeletal muscles rose up. We draw a clear potential crosstalk pathway that, increased 11βHSD1 secreted by excess AT will promote the expression of the major inhibitor MSTN by activating corticosterone to cortisol, leading to the growth inhibition of skeletal muscle. Overall, this research announces how obesity affects skeletal muscle growth in a crosstalk sight. Male and female Bama minipigs, aged 6 months at the start of the study, were divided into the following two groups for 23 months of treatment. Bama minipigon control (CD group, N=3) were fed standard pig chow. The experimental group (N=6) were fed high-fat high-sucrose diet (53% basal diet, 37% sucrose, 10% lard, HFHSD).
2014-10-15 | E-GEOD-62312 | biostudies-arrayexpress
Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Transcriptional profiling of muscle in treated and untreated wild-type and R6/2 mice was performed to analyze the effect of the ActRIIB decoy on genes and pathways involved in maintaining normal muscle physiology as well as those dysregulated due to the mutant HTT gene mutation.
2017-10-29 | GSE81367 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant condition that is characterised by a progressive degeneration and weakness of skeletal muscle fibers. The underlying cause of FSHD has been attributed to inappropriate expression of the transcription factor double homeobox (Dux); however, the mechanisms leading to myopathy in response to Dux expression remain incompletely understood. To study the acute effects of Dux activation in mammalian skeletal muscle fibers, we generated a recombinant adeno-associated viral vector allowing tunable Dux expression. Consistent with previous findings, we confirmed that the ectopic expression of Dux in mouse skeletal muscle results in a degenerative myopathy. Building on these findings, we observed that the acute expression of Dux in muscle fibers causes profound transcriptome changes prior to the onset of pathology. Furthermore, muscles expressing Dux display elevated levels of the TGF-beta superfamily member, Myostatin and increased Smad2/3 activity. Notably, inhibition of Myostatin is sufficient to prevent Dux-induced myopathy. Collectively, these findings support further investigation of interventions targeting the Myostatin-Smad2/3 pathway as prospective approaches to treating myopathy associated with Dux mis-expression.
2021-12-31 | GSE108828 | GEO