Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA395585 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle function is vital to movement, thermogenesis and metabolism. Muscle fibers differ in contractile ability, mitochondrial content and metabolic properties and muscle fiber transition influences muscle function. However, the molecular mechanisms regulating muscle fiber transition in muscle function are unclear. Here, in over 150 human muscle samples, we observed that markers of oxidative muscle fiber and mitochondria correlate positively with PPARGC1 and CDK4, and, negatively with CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing an overactive Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, are longer, leaner, exhibit increased oxidative myofibers with superior mitochondrial energetics, display enhanced muscle glucose uptake, and are protected from obesity and diabetes. In contrast, Cdk4-deficiency, or skeletal muscle-specific deletion of Cdk4’s transcriptional target, E2F3, reduces oxidative myofiber numbers, deteriorates mitochondrial function and exercise capacity, while increasing diabetes susceptibility. E2F3 activates the PPARGC1 promoter and CDK4/E2F3/PPARGC1 levels correlate positively with exercise and fitness, and negatively with adiposity, insulin resistance and lipid accumulation in muscle. These findings provide insight into oxidative muscle fiber transition and function that is of relevance to metabolic and muscular diseases.
2023-07-06 | GSE185154 | GEO
Project description:Skeletal muscle insulin resistance and β-cell dysfunction are signature features of type 2 diabetes (T2D) pathogenesis. We previously demonstrated a pivotal role for the cell cycle kinase, Cdk4, in regulation of β-cell mass. Here, we demonstrate that Cdk4R/R mice, which harbor constitutively active Cdk4 kinase, are resistant to obesity and diabetes. The metabolic protection is associated with Cdk4 promoting the numbers and regeneration potential of slow/oxidative muscle fibers, improved muscle mitochondrial bioenergetics and elevated E2F3 and PGC-1α expression in muscle. In contrast, muscle-specific E2F3 knockout mice exhibit poor exercise capacity and susceptibility to obesity and diabetes. Exercise induces levels of Cdk4/E2F3/PGC-1α, while those levels are suppressed in obesity. Also, levels of E2F3/PGC-1α negatively correlate with adiposity, insulin resistance and lipid accumulation in human muscle biopsies. These findings are supportive of an important role for Cdk4/E2F3 in muscle fiber type development and metabolism with therapeutic potential for metabolic and muscular diseases.
2023-07-06 | GSE101820 | GEO
Project description:CDKN2A-CDK4-E2F3 dependent oxidative skeletal muscle fiber transition in myogenesis, movement, and metabolism
| PRJNA767835 | ENA
Project description:Thyroid hormones are important for homeostatic control of energy metabolism and body temperature. Although skeletal muscle is considered an important site for thyroid action, the contribution of thyroid hormone receptor signaling, in muscle, to whole-body energy metabolism and body temperature has not been resolved. Here, we show that thyroid hormone-induced increase in energy expenditure requires thyroid hormone receptor alpha 1 (TRa1) in skeletal muscle, but that thyroid hormone induced elevation in body temperature is independent of muscle-TRa1. In slow-twitch soleus muscle, ablation of TRa1 leads to an altered fiber type composition toward a more oxidative phenotype, which, however, does not influence running capacity or motivation to voluntary running. RNA-sequencing of soleus muscle from WT mice and TRaHSACre mice revealed differentiated transcriptional regulation of genes associated with muscle thermogenesis, such as sarcolipin and UCP3, thus providing molecular clues pertaining to the mechanistic underpinnings of TRa1-linked control of whole-body metabolic rate. Together, this work establishes a fundamental role for skeletal muscle in thyroid hormone-stimulated increase in whole-body energy expenditure.
2020-09-21 | GSE146336 | 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: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:In the present study, we explored whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (CthΔskm) mice. Metabolomics coupled with transcriptome showed that CthΔskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth-floxed mice (Cthf/f) mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. CthΔskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in CthΔskm+HFD mice. Omics analysis showed differential pathways enriched between CthΔskm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in CthΔskm+HFD mice compared to Cthf/f+HFD mice. Our data indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.
2024-05-11 | GSE254704 | GEO
Project description:The three estrogen related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle have not been elucidated. To address the roles and significance of ERRs for skeletal muscle mitochondria and muscle function, we generated mice lacking combinations of ERRs specifically in skeletal muscle. We then compared the impact of ERR loss on the transcriptomes of EDL and soleus, i.e., muscles rich in glycolytic or oxidative fibers, respectively. Our findings highlight an essential role of ERRs for skeletal muscle oxidative metabolism and identify broad classes of ERR-dependent gene programs in muscle. They also suggest a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, with ERR isoform-specific phenotypes being driven primarily, but not exclusively, by their relative levels in different muscles. To compare the relative contributions of ERRs for oxidative capacity in glycolytic and oxidative skeletal muscles, we generated mice lacking one or two ERRs specifically in skeletal muscle. We then performed gene expression profiling analysis using data obtained from RNA-seq of soleus and EDL muscles of WT and ERR KO mice .
2023-01-09 | GSE214876 | GEO
Project description:Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle. This metabolic reprogramming was linked with reduced expression of p53-dependent genes that mediate apoptosis and ferroptosis, which preserved cell viability in response to lipotoxicity. Mechanistically, impaired mitochondrial metabolism reduced acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis, while redox drivers of ferroptosis were also reduced. Overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice enhanced oxidative capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of the oxidative state of skeletal muscle, and that this metabolic reprogramming, considered deleterious for normal metabolism, is critical to preserve muscle integrity in response to lipotoxicity.
2022-10-11 | GSE215185 | GEO
Project description:The obese, insulin resistant state is characterized by impairments in lipid metabolism. Dietary polyphenols might improve these deteriorations. We have previously shown that 3-days supplementation of combined Epigallocatechin-gallate and Resveratrol (E+R) increased energy expenditure, which was accompanied by improved metabolic flexibility after a high-fat mixed-meal (HFMM) in men. The present study aimed to investigate whether these short-term effects translate into longer-term improvement of insulin sensitivity and lipid metabolism. In this randomized, double-blind study, 42 overweight subjects (21 male, 38±2 yrs, BMI 29.7±0.5 kg/m2, HOMA-IR 2.1±0.2) received either E+R (300 and 80 mg/d, respectively) or placebo (PLA) for 12 weeks (3 months). Before (t0) and after (t3) intervention, tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with stable isotope infusion. Fasting and postprandial (HFMM) lipid metabolism was assessed using indirect calorimetry and blood sampling. Adipose tissue and skeletal muscle lipolysis was measured using microdialysis in men and skeletal muscle biopsies were collected to assess mitochondrial function and gene expression alterations via microarray analysis. E+R supplementation increased fasting (P=0.06) and postprandial (P=0.03) fat oxidation but did not alter energy expenditure compared to PLA. This was accompanied by an E+R-induced increase in oxidative capacity in permeabilized muscle fibers (p<0.05). Moreover, E+R supplementation attenuated the increase in plasma triacylglycerol concentration that was observed in the PLA group (AUC, p<0.05), and tended to decrease visceral fat mass (P=0.09). Finally, insulin-stimulated glucose disposal and suppression of endogenous glucose production were not affected by E+R supplementation. 12 weeks E+R supplementation increased whole-body fat oxidation and skeletal muscle oxidative capacity, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. To identify pathways that may underlie the E+R-induced improvement of skeletal muscle mitochondrial capacity, we performed microarray analysis on skeletal muscle biopsies (vastus lateralis muscle), collected before and after 12-weeks E+R or PLA treatment. Gene Set Enrichment Analysis (GSEA) indicated that the most upregulated pathways after E+R supplementation were related to the citric acid cycle and respiratory electron transport chain, while pathways related to carbohydrate metabolism were upregulated in the PLA group. In this randomized, double-blind placebo-controlled, parallel intervention trial, subjects received either a combination of E+R supplements (INTV, 282 mg/d and 80 mg/d, respectively) or placebo (PLA, partly hydrolyzed microcrystalline cellulose-filled capsules) for a period of 12 weeks (3 months) to assess effects of E+R supplementation on tissue-specific insulin sensitivity (primary outcomes) and fasting and postprandial substrate metabolism (secondary outcomes). Skeletal muscle (m. vastus lateralis) biopsies were taken under local anesthesia during fasting conditions before (t0) and after the 12-weeks (t3) intervention period. Extraxted RNA was hybridized on HTA 2.0 Affymetrix arrays and microarray analysis was performed on paired sample sets for 27 subjects (p, PLA n = 14; E+R n = 13).
2016-08-03 | E-GEOD-71614 | biostudies-arrayexpress