Tbx15 Controls Skeletal Muscle Fiber Type Determination and Muscle Metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE70489 | GEO | 2015/07/03
SECONDARY ACCESSION(S): PRJNA288810
REPOSITORIES: GEO
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Project description:Skeletal muscle is composed of both slow-twich oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function, and eventually whole-body physiology. In the present study, we find that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibers, associated with a small increase in the number of oxidative fibers. This shift in fiber composition results in muscles with slower myofiber contraction and relaxation, and also results in decreased whole-body oxygen consumption, decreased spontaneous activity, increased adiposity, and glucose intolerance. In order to identify genes regulated by Tbx15, we utilized C2C12 myoblasts with either a stable retroviral over-expression or stable lentiviral knockdown of Tbx15. RNA was extracted and biotin labelled complementary RNA (cRNA) was prepared from three independent transfections of the four stable C2C12 myoblast cell lines: shTbx15, shGFP, pBABE-Empty-puro, pBABE-Tbx15-puro. Cells were collected at 90% confluency, and subjected to microarray analysis. Affymetrix M430 2.0 Chips were used.
2015-07-03 | E-GEOD-70489 | biostudies-arrayexpress
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 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:Skeletal muscle must perform a wide range of kinds of work, and different fiber types have evolved to accommodate these different tasks. The attributes of fibers are determined in large part by the coordinated regulation of oxidative capacity, as reflected by mitochondrial content, and the specific makeup of myofibrillar proteins. Adult muscle fibers contain four myosin heavy chain isotypes: I, IIa, IIx and IIb. Type I and IIa fibers have slower twitches and are rich in mitochondria, while type IIb fibers are fast-twitch and predominantly glycolytic. The intermediate IIx fibers are less well understood. Previous work had shown that the transcriptional coactivator PGC-1 alpha could drive the formation of type I and IIa muscle fibers. We show here that mice with transgenic expression of PGC-1 beta in skeletal muscle results in marked induction of IIx fibers. The fibers in transgenic mice are rich in mitochondria and are highly oxidative. As a result, PGC-1 beta transgenic animals can perform oxidative activity for longer and at higher work loads than wild type animals. In cell culture, PGC-1 beta coactivates the MEF2 family of transcription factors to stimulate the MHC IIx promoter. Together, these data indicate that PGC-1 beta is sufficient to drive the formation in vivo of highly oxidative fibers with type IIx characteristics.
2007-04-02 | E-MEXP-939 | biostudies-arrayexpress
Project description:Skeletal muscle fibers regulate surrounding endothelial cells (EC) via secretion of numerous angiogenic factors, including extracellular vesicles (SkM-EV). Muscle fibers are broadly classified as oxidative (OXI) or glycolytic (GLY) depending on their metabolic characteristics. OXI fibers secrete more pro-angiogenic factors and have greater capillary densities than GLY fibers. OXI muscle secretes more EV than GLY, however it is unknown whether muscle metabolic characteristics regulate EV contents and signaling potential. Extracellular vesicles were isolated from primarily oxidative or glycolytic muscle tissue in mice. MicroRNA (miR) sequencing was done to determine SkM-EV miR contents and cultured endothelial cells were treated with OXI- and GLY-EV to investigate angiogenic signaling potential. There were considerable differences in miR contents between OXI- and GLY-EV and pathway analysis identified that OXI-EV miR were predicted to positively regulate multiple endothelial-specific pathways including nitric oxide (NO) and vascular endothelial growth factor (VEGF) pathways, compared to GLY-EV miRs. OXI-EV improved EC migration (+19%) and tube formation (length: +20%; # of tubes +35%) compared to GLY-EV. These benefits may have been NO pathway mediated, as OXI-EV increased phosphorylation of endothelial nitric oxide synthase (eNOS) and treatment of ECs with the NOS inhibitor L-NAME abolished differences in migration and tube formation between OXI- and GLY-EV. This is the first report to show widespread differences in miR contents between SkM-EV isolated from metabolically different muscle tissue and the first to demonstrate that oxidative muscle tissue secretes EV with greater angiogenic signaling potential than glycolytic muscle tissue.
2022-10-26 | GSE216121 | GEO
Project description:Background: skeletal muscle is a complex, versatile tissue composed of a variety of functionally diverse fiber types. Although the biochemical, structural and functional properties of myofibers have been the subject of intense investigation for the last decades, understanding molecular processes regulating fiber type diversity is still complicated by the heterogeneity of cell types present in the whole muscle organ. Methodology/Principal Findings: we have produced a first catalogue of genes expressed in mouse slow-oxidative (type 1) and fast-glycolytic (type 2B) fibers through transcriptome analysis at the single fiber level (microgenomics). Individual fibers were obtained from murine soleus and EDL muscles and initially classified by myosin heavy chain isoform content. Gene expression profiling on high density DNA oligonucleotide microarrays showed that both qualitative and quantitative improvements were achieved, compared to results with standard muscle homogenate. First, myofiber profiles were virtually free from non-muscle transcriptional activity. Second, thousands of muscle-specific genes were identified, leading to a better definition of gene signatures in the two fiber types as well as the detection of metabolic and signaling pathways that are differentially activated in specific fiber types. Several regulatory proteins showed preferential expression in slow myofibers. Discriminant analysis revealed novel genes that could be useful for fiber type functional classification. Conclusions/Significance: as gene expression analyses at the single fiber level significantly increased the resolution power, this innovative approach would allow a better understanding of the adaptive transcriptomic transitions occurring in myofibers under physiological and pathological conditions.
2011-07-21 | GSE23244 | GEO
Project description:Skeletal muscle myofibers, categorized into slow-twitch (type I) and fast-twitch (type II) fibers based on myosin heavy chain (MHC) isoforms, exhibit varying fatigue resistance and metabolic reliance. Type I myofibers are fatigue-resistant with high mitochondrial density and oxidative metabolism, while Type II myofibers fatigue quickly due to glycolytic metabolism and fewer mitochondria. Endurance training induces remodeling of myofiber and mitochondrial, increasing slow-twitch myofibers and enhancing mitochondrial oxidative capacity, improving muscle fitness. In our study, conducted using single-cell techniques, we delved deeply into the transcriptomic differences between type I and type IIb myofibers. In response to endurance training, type I myofibers exhibited heightened signals in essential adaptive responses, such as fatty acid oxidation, mitochondrial biogenesis, and protein synthesis, compared to type IIb myofibers. By analyzing untrained myofibers, we identified specific signaling pathways that explain the differences in their responses to endurance training. These findings provide nuanced insights into the molecular mechanisms governing endurance adaptations in fast and slow-twitch muscles, offering valuable guidance for tailored exercise routines and potential therapeutic interventions.
2024-12-31 | GSE244547 | GEO
Project description:Skeletal muscle is highly developed after birth, consisting of glycolytic fast- and oxidative slow-twitch fibers; however, the mechanisms of fiber type-specific differentiation are poorly understood. Here, we found an unexpected role for mitochondrial fission in the differentiation of fast-twitch oxidative fibers. Depletion of the mitochondrial fission factor dynamin-related protein 1 (Drp1) in mouse skeletal muscle and cultured myotubes resulted in the specific reduction of fast-twitch muscle fibers independently of respiratory function. Altered mitochondrial fission caused the activation of the Akt/mammalian target of rapamycin (mTOR) pathway via the mitochondrial accumulation of mTOR complex 2 (mTORC2), and rapamycin administration rescued the reduction of fast-twitch fibers in vivo and in vitro. Under Akt/mTOR activation, the mitochondria-related cytokine growth differentiation factor-15 was upregulated, which repressed fast-twitch fiber differentiation. Our findings reveal a novel role for mitochondrial dynamics in the activation of mTORC2 on mitochondria, resulting in the differentiation of muscle fibers.
2023-04-01 | GSE228362 | GEO
Project description:MHC-I overexpression in muscle biopsies is a hallmark of inflammatory myopathies.However the mechanisms of MHC-I overexpression in each disease is not well understood. Microarray analysis from MHC-I-microdissected myofibers showed a differential expression signature in each inflammatory myopathy. Innate immunity and IFN-I pathways are upregulated vs healthy controls, specifically in dermatomyositis (DM). RNA from MHC-I-positive myofibers were obtained from muscle biopsies of 5 patients with dermatomyositis, 5 with polymyositis, 4 with inclusion body myositis and normal looking fibers from healthy controls.
2013-12-01 | E-GEOD-48280 | biostudies-arrayexpress
Project description:Background: skeletal muscle is a complex, versatile tissue composed of a variety of functionally diverse fiber types. Although the biochemical, structural and functional properties of myofibers have been the subject of intense investigation for the last decades, understanding molecular processes regulating fiber type diversity is still complicated by the heterogeneity of cell types present in the whole muscle organ. Methodology/Principal Findings: we have produced a first catalogue of genes expressed in mouse slow-oxidative (type 1) and fast-glycolytic (type 2B) fibers through transcriptome analysis at the single fiber level (microgenomics). Individual fibers were obtained from murine soleus and EDL muscles and initially classified by myosin heavy chain isoform content. Gene expression profiling on high density DNA oligonucleotide microarrays showed that both qualitative and quantitative improvements were achieved, compared to results with standard muscle homogenate. First, myofiber profiles were virtually free from non-muscle transcriptional activity. Second, thousands of muscle-specific genes were identified, leading to a better definition of gene signatures in the two fiber types as well as the detection of metabolic and signaling pathways that are differentially activated in specific fiber types. Several regulatory proteins showed preferential expression in slow myofibers. Discriminant analysis revealed novel genes that could be useful for fiber type functional classification. Conclusions/Significance: as gene expression analyses at the single fiber level significantly increased the resolution power, this innovative approach would allow a better understanding of the adaptive transcriptomic transitions occurring in myofibers under physiological and pathological conditions. EDL and soleus muscles were incubated with type I collagenase to dissociate intact myofibres that were separated under stereo microscope from the bulk of hyper contracted fibres. Isolated myofibres were divided in two parts: one was immersed in Laemmli buffer for fibre typing; the other was placed in RNA extraction buffer for RNA amplification. We analyzed the transcription profiles of 10 biological replicas of type 2B single muscle fibres from EDL and 10 biological replicas of type 1 single muscle fibres from soleus. Microarray competitive hybridizations were carried out against an artificial control with a balanced composition of type 1 and type 2B fibres (20 hybridizations). Each oligonucleotide is spotted in two replicates on the glass slide, so for every data two intra-slide replicas are present. The control was created as follows: three couples of soleus and EDL muscles were removed from 3 different mice and treated with collagenase. Total RNA was extracted separately from EDL and soleus muscles. By mixing about 1/3 RNA from EDL and 2/3 RNA from soleus muscles the control had approximately the same contributions of type 1 and type 2B fibres. Purified RNA samples from single fibres and from control were amplified twice using the Amino Allyl MessageAmpM-bM-^DM-" II aRNA Amplification Kit (Ambion).
2011-07-20 | E-GEOD-23244 | biostudies-arrayexpress