Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134519 | GEO | 2019/12/31
REPOSITORIES: GEO
Similar Datasets
Project description:Sirtuin1 (Sirt1) in skeletal muscle (SK) and fat protects against metabolic damage by stimulating insulin sensitivity. Here we report that mice with selective deletion of endothelial Sirt1 (E-Sirt1-KO) paradoxically exhibit heightened whole-body insulin sensitivity. Akt phosphorylation, glucose uptake, and glycolysis are boosted in SK and brown adipose tissue (BAT) of E-Sirt1-KO mice. E-Sirt1-KO mice have higher energy expenditure and are partially protected from high-fat diet-induced insulin resistance. Enhanced insulin sensitivity and peripheral tissue Akt phosphorylation in E-Sirt1-KO mice is transferrable to wild-type mice via the systemic circulation after surgical parabiosis. Silencing of Sirt1 in endothelial cells upregulates transcription of the F-actin-binding protein thymosin beta-4 (Tβ4), whose secretion activates Akt in skeletal myotubes. Sirt1 downregulation stimulates endothelial Tβ4 transcription through inhibition of autophagy and upregulation of nuclear factor-kappa B signaling. Thus, unlike Sirt1 in skeletal muscle and fat, endothelial Sirt1 curtails whole-body insulin sensitivity by inhibiting expression of secreted Tβ4.
2023-08-07 | PXD030565 | Pride
Project description:In contrast to the well-established role of oxidative muscle fibers in regulating fatty acid oxidation and whole body metabolism, little is known that about the function of fast/glycolytic muscle fibers in these processes. Here, we generated a skeletal muscle-specific, conditional transgenic mouse expressing a constitutively-active form of Akt1. Transgene activation led to muscle hypertrophy due to the growth of type IIb muscle fibers, which was accompanied by an increase in strength. These mice were then used to assess the consequence of building fast/glycolytic muscle fibers on adiposity and metabolism. Akt1 transgene induction in obese mice resulted in reductions in body weight and fat mass, a resolution of hepatic steatosis and improved metabolic parameters. These effects were achieved independent of changes in physical activity and levels of food consumption. Akt1-mediated skeletal muscle growth opposed the effects of high fat/sucrose diet on transcript expression patterns in the liver, and increased hepatic fatty acid oxidation and ketone body production. Our findings indicate that an increase in fast/glycolytic muscle mass can result in the regression of obesity and obesity-related metabolic disorders in part through its ability to alter fatty acid metabolism in remote tissues. Experiment Overall Design: 11 samples are included in this series. 3 wild-type mice fed on a normal diet, 4 wild-type mice fed on a HF diet, and 4 Akt1 double transgenic mice fed on a HF diet. All samples are on the mixed background.
2008-06-16 | E-GEOD-9484 | biostudies-arrayexpress
Project description:Myostatin (GDF8) is a member of the TGF-beta family of proteins which is predominantly expressed in skeletal muscle and acts as a negative regulator of muscle mass. Inhibition of myostatin leads to muscle hypertrophy and has been shown to mitigate insulin resistance in mouse models of type 2 diabetes, although the mechanisms underlying this effect are unclear. We found that myostatin inhibition by AAV-mediated overexpression of the myostatin propeptide improves skeletal muscle insulin sensitivity in mice made insulin-resistant by high fat diet feeding. To gain insight into potential gene expression changes responsible for this effect, we performed microarray analysis on skeletal muscle samples from high fat diet-fed mice with and without myostatin inhibition.
2020-05-29 | GSE130622 | GEO
Project description:In contrast to the well-established role of oxidative muscle fibers in regulating fatty acid oxidation and whole body metabolism, little is known that about the function of fast/glycolytic muscle fibers in these processes. Here, we generated a skeletal muscle-specific, conditional transgenic mouse expressing a constitutively-active form of Akt1. Transgene activation led to muscle hypertrophy due to the growth of type IIb muscle fibers, which was accompanied by an increase in strength. These mice were then used to assess the consequence of building fast/glycolytic muscle fibers on adiposity and metabolism. Akt1 transgene induction in obese mice resulted in reductions in body weight and fat mass, a resolution of hepatic steatosis and improved metabolic parameters. These effects were achieved independent of changes in physical activity and levels of food consumption. Akt1-mediated skeletal muscle growth opposed the effects of high fat/sucrose diet on transcript expression patterns in the liver, and increased hepatic fatty acid oxidation and ketone body production. Our findings indicate that an increase in fast/glycolytic muscle mass can result in the regression of obesity and obesity-related metabolic disorders in part through its ability to alter fatty acid metabolism in remote tissues. Keywords: genetic modification
2007-11-02 | GSE9484 | GEO
Project description:Branched-chain amino acids (BCAA) have emerged as predictors of type 2 diabetes (T2D). However, their potential role in the pathogenesis of insulin resistance and T2D remains unclear. By integrating data from skeletal muscle gene expression and metabolomic analyses, we demonstrate evidence for perturbation in BCAA metabolism and fatty acid oxidation in skeletal muscle from insulin-resistant humans. Experimental modulation of BCAA flux in cultured cells alters fatty acid oxidation in parallel. Furthermore, heterozygosity for the BCAA metabolic enzyme methylmalonyl-CoA mutase (MUT) alters muscle lipid metabolism in vivo, resulting in increased muscle triacylglycerol (TAG) accumulation and increased body weight after high-fat feeding. Together, our results demonstrate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by reducing fatty acid oxidation and increasing TAG accumulation.
2017-02-09 | GSE66766 | 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:We demonstrate whole body inflammation (miR146a-/-) exacerbated inactivity-induced fat gain and glucose dysregulation, while muscle specific MyD88 KO mitigated these outcomes in female mice. Higher gene expression of Igf1 and decreased expression of Ip6k3 in muscle of MyD88 KO female mice may explain enhancement of glucose uptake in the soleus. Whereas protection from fat accumulation may be related to visceral fat gene changes in adipose tissue expansion (Prc1↓, Gulp1↑, Anxa2↓, Cav2↓, EHD1↓), adipose beiging (Fgf10↑), metainflammation (Hmox1↓), and genes involved in perfusion. Of noteworthy to mention, two genes decreased in common between muscle and fat with the ablation of muscle MyD88. These were expression of the negative regulator for GLUT4 translocation, Ralgapa2, and uncharacterized 993011J21Rik2, a potential interferon interacting gene. We conclude that future therapeutic strategies for prevention or treatment of obesity and metabolic disturbances in populations unable to be physically active should focus on further understanding how skeletal muscle inflammation communicates with fat storage depots, and how this cross-talk is influenced by sex hormones.
2019-12-30 | GSE138940 | GEO
Project description:Metabolically healthy skeletal muscle is characterized by the ability to switch easily between glucose and fat oxidation, whereas loss of this ability seems to be related to insulin resistance. The aim of this study was to investigate whether different fatty acids (FAs) and the LXR ligand T0901317 affected metabolic switching in human skeletal muscle cells (myotubes). Pretreatment of myotubes with eicosapentaenoic acid (EPA) increased suppressibility, the ability of glucose to suppress FA oxidation, and metabolic flexibility, the ability to increase FA oxidation when changing from “fed” to “fasted” state. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was increased after pretreatment with EPA, linoleic acid (LA) and palmitic acid (PA). T0901317 counteracted the effect of EPA on suppressibility and adaptability, but did not affect these parameters alone. EPA itself accumulated less, however, EPA, LA, OA and T0901317 increased the number of lipid droplets (LDs) in myotubes, whereas LD size and mitochondria amount were independent of pretreatment. Microarray analysis showed that EPA regulated more genes than the other FAs. Some pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a possible favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization. Keywords: Analysis of target gene regulation by using microarrays. Primary human myotubes, derived from 3 healthy, female donors, were preincubated with different fatty acids (oleic acid [OA], palmitic acid [PA], eicosapentaenoic acid [EPA] or linoleic acid [LA], each at 100 µM) or bovine serum albumin [BSA] (40 µM) for 24 h.
2010-06-23 | E-GEOD-18589 | biostudies-arrayexpress
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. Keywords: genetic modification
2006-09-08 | GSE5777 | GEO
Project description:Skeletal muscle is the largest tissue in the body and mainly relies on mitochondrial oxidative metabolism for sustainable ATP production. Reduced oxygen availability, also known as hypoxia, can be caused by high altitude or pathology and impacts mitochondria. Whereas long-term hypoxia results in increased reliance on glycolysis, reduced fatty acid oxidation and a decreased skeletal muscle mass, the in vivo mechanisms of adaptation of skeletal muscle to acute hypoxia remain elusive. Therefore, we aimed to provide an integrated description of the response of the M. gastrocnemius to acute hypoxia. Fasted male C57BL/6JOlaHsd mice were exposed to 12% oxygen representing normobaric hypoxia versus 21% oxygen (normoxia) for six hours (n=12 mice per group). Whole-body energy metabolism and the transcriptome response of the M. gastrocnemius mice was analyzed and confirmed by acylcarnitine determination and RT-qPCR. On whole-body level, six hours of hypoxia reduced energy expenditure, increased blood glucose and tended to further decrease the respiratory exchange ratio (RER). Whole genome transcriptome analysis revealed upregulation of the FOXO signalling pathway including an increased expression of Trib3, which was positively correlated with blood glucose. Apart from upregulation of Cpt1a, which negatively correlated with the RER, and SLC25a25 (Cact), fatty acid β-oxidation was not regulated. Together with significantly increased muscle C14 and C16-acylcarnitines this supports no increased fatty acid catabolism in muscle. In addition, the hypoxia-induced FOXO activation could also be connected to altered gene profiles related to fiber type switching, extracellular matrix remodelling, muscle differentiation and the denervation of neuromuscular junctions (NMJ). Conclusively, our results suggest that an acute, six hours exposure of mice to hypoxia impacts M. gastrocnemius via FOXO1, initiating alterations in skeletal muscle that may ultimately contribute to tissue remodelling. This supports an early role of hypoxia in tissue alterations in hypoxia-associated conditions such as aging and obesity. The observed impact of hypoxia on denervated NMJ is novel and warrants further investigation.
2023-10-23 | GSE228719 | GEO