Similar Datasets
Project description:To study the effect of Sidt2 protein deficiency on skeletal muscle, we developed skeletal musclespecific Sidt2 gene knockout mouse model using Cre under the control of the MCK promoter We used microarrays to detail the changes of gene expression.
2018-04-17 | GSE113167 | GEO
Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor beta (PPARb) in skeletal muscle of transgenic mice that overexpressed PPARb. The following abstract from the submitted manuscript describes the major findings of this work. The Nuclear Receptor Transcription Factor PPARbeta/delta Programs Muscle Glucose Metabolism. Zhenji Gan, Eileen Burkart-Hartman, Dong-Ho Han, Brian Finck, Teresa C. Leone, John Holloszy, and Daniel P. Kelly. To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors, PPARalpha (MCK-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase (Ldh)b/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, interacts with the exercise inducible kinase, AMP-activated protein kinase (AMPK), to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A), in a PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARbeta/delta mice had lower circulating levels of lactate compared to non-transgenic controls, while exhibiting supranormal performance on a high intensity exercise regimen. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training. Keywords: muscle, exercise, nuclear receptors, glucose metabolism, gene regulation RNA from two wild-type (non-transgenic (NTG)) and two PPARbeta overexpressing (MCK-PPARb) mice was analyzed. Two replicates of each are provided.
2011-12-12 | E-GEOD-29055 | biostudies-arrayexpress
Project description:This experiment was conducted to identify target microRNAs of the peroxisome proliferator-activated receptor (PPAR) in skeletal muscle of transgenic mice that overexpressed PPARalpha or PPARbeta. We have recently demonstrated that skeletal muscle-specific PPARb transgenic (MCK-PPARb) mice exhibit increased exercise endurance, whereas MCK-PPARa mice have reduced exercise performance. Accordingly, we sought to determine whether PPARb and PPARa drive distinct programs involved in muscle fiber type determination. Myosin heavy chain (MHC) immunohistochemical staining of soleus muscle revealed a marked increase in type 1 fibers in the MCK-PPARb muscle compared to non-transgenic (NTG) littermates but a profound reduction in MCK-PPARa muscle. miRNA profiling revealed that levels of miR-208b and miR-499 were increased in MCK-PPARb muscle but reduced in MCK-PPARa muscle. miR-208b and miR-499, which are embedded in the Myh7 and Myh7b genes, respectively, have been shown previously to regulate slow-twitch muscle genes. Lastly, combined inhibition of miR-208b and miR-499 abolished the enhancing effects of PPARb on MHC1 expression in skeletal myotubes, while forced expression of miR-499 in MCK-PPARa muscle completely reversed the type 1 fiber program and exercise capacity. Taken together, these findings demonstrate that miR-208b and miR-499 are necessary to mediate the effects of PPARb and PPARa on muscle fiber type determination. Comparison of microRNA expression from soleus muscles isolated from wild-type (non-transgenic (NTG)) and PPARalpha-overexpressing (MCK-PPARa) mice, and comparison of microRNA expression from soleus muscles isolated from wild-type (NTG) and PPARbeta-overexpressing (MCK-PPARb) mice. Three replicates of each are analyzed.
2013-05-09 | E-GEOD-36498 | biostudies-arrayexpress
Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor beta (PPARb) in skeletal muscle of transgenic mice that overexpressed PPARb. The following abstract from the submitted manuscript describes the major findings of this work. The Nuclear Receptor Transcription Factor PPARbeta/delta Programs Muscle Glucose Metabolism. Zhenji Gan, Eileen Burkart-Hartman, Dong-Ho Han, Brian Finck, Teresa C. Leone, John Holloszy, and Daniel P. Kelly. To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors, PPARalpha (MCK-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase (Ldh)b/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, interacts with the exercise inducible kinase, AMP-activated protein kinase (AMPK), to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A), in a PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARbeta/delta mice had lower circulating levels of lactate compared to non-transgenic controls, while exhibiting supranormal performance on a high intensity exercise regimen. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training. Keywords: muscle, exercise, nuclear receptors, glucose metabolism, gene regulation
2011-12-12 | GSE29055 | GEO
Project description:This experiment was conducted to identify target microRNAs of the peroxisome proliferator-activated receptor (PPAR) in skeletal muscle of transgenic mice that overexpressed PPARalpha or PPARbeta. We have recently demonstrated that skeletal muscle-specific PPARb transgenic (MCK-PPARb) mice exhibit increased exercise endurance, whereas MCK-PPARa mice have reduced exercise performance. Accordingly, we sought to determine whether PPARb and PPARa drive distinct programs involved in muscle fiber type determination. Myosin heavy chain (MHC) immunohistochemical staining of soleus muscle revealed a marked increase in type 1 fibers in the MCK-PPARb muscle compared to non-transgenic (NTG) littermates but a profound reduction in MCK-PPARa muscle. miRNA profiling revealed that levels of miR-208b and miR-499 were increased in MCK-PPARb muscle but reduced in MCK-PPARa muscle. miR-208b and miR-499, which are embedded in the Myh7 and Myh7b genes, respectively, have been shown previously to regulate slow-twitch muscle genes. Lastly, combined inhibition of miR-208b and miR-499 abolished the enhancing effects of PPARb on MHC1 expression in skeletal myotubes, while forced expression of miR-499 in MCK-PPARa muscle completely reversed the type 1 fiber program and exercise capacity. Taken together, these findings demonstrate that miR-208b and miR-499 are necessary to mediate the effects of PPARb and PPARa on muscle fiber type determination.
2013-05-09 | GSE36498 | GEO
Project description:We analyzed the gene expression changes that result from mitochondria overloaded by unfolded proteins in skeletal muscles. Mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC) is a known protein degraded by LONP1 and an established model for studying mitochondrial proteostasis imbalance. We generated transgenic mice overexpressing ΔOTC specifically in skeletal muscle using the muscle creatine kinase promoter (MCK-ΔOTC). Transcriptome analysis was performed by whole-genome gene expression profiling experiments in muscles from the MCK-ΔOTC mice and NTG littermate controls. The comparative mRNA profiling strategy revealed extensive genomic reprogramming in MCK-ΔOTC muscles, with 1051 genes up- and 519 genes down-regulated (1.5-fold change and p<0.05), respectively. GO analysis of the regulated genes in MCK-ΔOTC muscles revealed significant enrichment in unfolded protein response as well as RNA processing process. These data suggest that mitochondria overloaded by ΔOTC unfolded proteins induce extensive genomic reprogramming in skeletal muscle
2022-07-28 | GSE192991 | GEO
Project description:We investigated the effect of weight loss maintenance (WLM) and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity prone rats, WLM reduced fat oxidative capacity and down-regulated genes involved in fat metabolism. After weight was regained in rats, the genes involved in fat metabolism were still reduced. Mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, were subjected to our WLM and weight regain paradigm. We found that mCK-hLPL attenuated weight regain by potentiating energy expenditure.Irrespective of genotype, weight regain suppressed dietary fat oxidation and down-regulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain.
2021-03-24 | GSE154943 | GEO
Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor alpha (PPARa) in skeletal muscle of transgenic mice that overexpressed PPARa. The following abstract from the published manuscript describes the major findings of this work. A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes.Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP. The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance. Experiment Overall Design: RNA from two wild-type (non-transgenic (NTG)) and two PPARalpha overexpressing (MCK-PPARa) mice was analyzed. Two replicates of each are provided.
2008-06-14 | E-GEOD-5777 | biostudies-arrayexpress
Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases. Gene expression of a total of 20 gastrocnemius samples from control (CON, n = 5), NCoR1 muscle-specific knockout (NCoR1 MKO, n = 5), wild type (WT, n = 5) and PGC-1alpha muscle-specific transgenic (PGC-1alpha mTg, n = 5) adult male mice was analyzed using GeneChip® Gene 1.0 ST Array System (Affymetrix). NCoR1 MKO and PGC-1alpha mTg samples were compared to CON and WT samples, respectively.
2013-01-08 | E-GEOD-40439 | biostudies-arrayexpress
Project description:Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with -cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. Methods: Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12-week-old mice with conditional -cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β-DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. Results: RNA transcripts were significantly altered in β-DKO mice compared to fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β-DKO mice compared to fl/fl controls (p = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the β-DKO mice. Supplementation of β-DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. Conclusions: Insulin insufficiency due to -cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.
2023-09-26 | E-MTAB-13315 | biostudies-arrayexpress