Obesity Impairs Embryonic Myogenesis by Enhancing BMP Signaling within the Dermomyotome.
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ABSTRACT:
SUBMITTER: Zhao L
PROVIDER: S-EPMC8596142 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Maternal exercise (ME) improves fetal and offspring muscle development, but mechanisms remain to be established. Since the thyroid hormone (TH) is critical for cell differentiation during embryonic development, we hypothesized that ME elevates TH receptor (THR) signaling in embryos, which promotes embryonic myogenesis. Methods: Female mice were exercised daily on a treadmill or received a daily TH, triiodothyronine (T3) injection. Embryos (embryonic day 12.5 [E12.5]) and P19 cells were used for studying effects of TH on embryonic myogenesis. TH levels in serum and embryos after ME or T3I were analyzed. Expression of TH signaling related genes and myogenic genes was assessed. THRα binding to the promoters of myogenic genes was investigated by chromatin immunoprecipitation-qantitative polymerase chain reaction (ChIP-qPCR). A CRISPR/CAS9 plasmid was utilized to knock out THRα in P19 cells. Results: ME elevated TH levels in both maternal circulation and embryos, which were correlated with enhanced TH signaling and myogenesis. At E12.5, both myogenic determinants (Pax3, Pax7) and myogenic regulatory factors (Myf5, Myod) were upregulated in ME embryos. ME increased THRα content and elevated messenger RNA (mRNA) expression of TH transporter Slc16a2 and deiodinase Dio2. In addition, the THRα binding to the promoters of Pax3/7 was increased. In P19 embryoid bodies, T3 promoted myogenic differentiation, which was abolished by ablating THRα. Furthermore, maternal daily injection of T3 at a level matching exercised mothers promoted embryonic myogenesis. Conclusions: ME promotes TH delivery to the embryos and enhances embryonic myogenesis, which is partially mediated by enhanced TH signaling in ME embryos.
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Project description:Mutations in the DMD gene lead to Duchenne muscular dystrophy, a severe X-linked neuromuscular disorder which manifests itself as young boys acquire motor functions. DMD is diagnosed after 2 to 4 years, but the absence of dystrophin has an impact before symptoms appear in patients, which poses a serious challenge in the optimization of standards of care. In this report, we investigated the early consequences of dystrophin deficiency during skeletal muscle development. We used single-cell transcriptome profiling to characterize the myogenic trajectory of human pluripotent stem cells and showed that DMD cells bifurcate to an alternative branch when they reach the somite stage. Here, dystrophin deficiency was linked to marked dysregulations of cell junction families involved in the cell state transitions characteristic of somitogenesis. Altogether, this work demonstrates that in vitro, dystrophin deficiency has early consequences during myogenic development, which should be considered in future therapeutic strategies for DMD.
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Project description:The development of a functional tissue requires coordination of the amplification of progenitors and their differentiation into specific cell types. The molecular basis for this coordination during myotome ontogeny is not well understood. Dermomytome progenitors that colonize the myotome first acquire myocyte identity and subsequently proliferate as Pax7-expressing progenitors before undergoing terminal differentiation. We show that the dynamics of sonic hedgehog (Shh) signaling is crucial for this transition in both avian and mouse embryos. Initially, Shh ligand emanating from notochord/floor plate reaches the dermomyotome, where it both maintains the proliferation of dermomyotome cells and promotes myogenic differentiation of progenitors that colonized the myotome. Interfering with Shh signaling at this stage produces small myotomes and accumulation of Pax7-expressing progenitors. An in vivo reporter of Shh activity combined with mouse genetics revealed the existence of both activator and repressor Shh activities operating on distinct subsets of cells during the epaxial myotomal maturation. In contrast to observations in mice, in avians Shh promotes the differentiation of both epaxial and hypaxial myotome domains. Subsequently, myogenic progenitors become refractory to Shh; this is likely to occur at the level of, or upstream of, smoothened signaling. The end of responsiveness to Shh coincides with, and is thus likely to enable, the transition into the growth phase of the myotome.
| S-EPMC3621491 | biostudies-literature
Project description:Xenopus myotome is formed by a first medial and lateral myogenesis directly arising from the presomitic mesoderm followed by a second myogenic wave emanating from the dermomyotome. Here, by a series of gain and loss of function experiments, we showed that Mef2d, a member of the Mef2 family of MADS-box transcription factors, appeared as an upstream regulator of lateral myogenesis, and as an inducer of dermomyotome formation at the beginning of neurulation. In the lateral presomitic cells, we showed that Mef2d transactivates Myod expression which is necessary for lateral myogenesis. In the most lateral cells of the presomitic mesoderm, we showed that Mef2d and Paraxis (Tcf15), a member of the Twist family of transcription factors, were co-localized and activate directly the expression of Meox2, which acts upstream of Pax3 expression during dermomyotome formation. Cell tracing experiments confirm that the most lateral Meox2 expressing cells of the presomitic mesoderm correspond to the dermomyotome progenitors since they give rise to the most dorsal cells of the somitic mesoderm. Thus, Xenopus Mef2d couples lateral myogenesis to dermomyotome formation before somite segmentation. These results together with our previous works reveal striking similarities between dermomyotome and tendon formation in Xenopus: both develop in association with myogenic cells and both involve a gene transactivation pathway where one member of the Mef2 family, Mef2d or Mef2c, cooperates with a bHLH protein of the Twist family, Paraxis or Scx (Scleraxis) respectively. We propose that these shared characteristics in Xenopus laevis reflect the existence of a vertebrate ancestral mechanism which has coupled the development of the myogenic cells to the formation of associated tissues during somite compartmentalization.
| S-EPMC3534117 | biostudies-literature
Project description:The dorsoventral gradient of BMP signaling plays an essential role in embryonic patterning. Zinc Finger SWIM-Type Containing 4 (zswim4) is expressed in the Spemann-Mangold organizer at the onset of Xenopus gastrulation and is then enriched in the developing neuroectoderm at the mid-gastrula stages. Knockdown or knockout of zswim4 causes ventralization. overexpression of zswim4 decreases, whereas knockdown of zswim4 increases the expression levels of ventrolateral mesoderm marker genes. Mechanistically, ZSWIM4 attenuates the BMP signal by reducing the protein stability of SMAD1 in the nucleus. Stable isotope labeling by amino acids in cell culture (SILAC) identifies Elongin B (ELOB) and Elongin C (ELOC) as the interaction partners of ZSWIM4. Accordingly, ZSWIM4 forms a complex with the Cul2-RING ubiquitin ligase and ELOB and ELOC, promoting the ubiquitination and degradation of SMAD1 in the nucleus. Our study identifies a novel mechanism that restricts BMP signaling in the nucleus.
| S-SCDT-10_1038-S44319-023-00046-W | biostudies-other
Project description:Insulin resistance is the hallmark of obese and type 2 diabetes patients. Defective insulin sensitivity in the liver results in increased glucsoe production, which is the major cause of hyperglycemia in diabetic patients. Increased lipopolysaccharide (LPS) leakage from the gut of diet-induced obesity causes insulin resisitance; moreover, activation of deacetylase Sirtuin1 restore insulin sensitivity in obesity. However, the mechanism resulting in insulin resistance by LPS remains poorly understood. Here, we show that Ep300 (P300) harboring an intrinsic acetyltransferase activity was rapidly induced in the liver of animals fed a high-fat diet, and the induction of Ep300 is through LPS-stimulated activation of ER stress. Induced Ep300 impairs insulin signaling by acetylating mediators in insulin signaling. Inhibition of P300 acetyltransferase activity improves insulin signaling. Thus, Ep300 acetyltransferase activity is a therapeutic target.
2017-05-08 | GSE86108 | GEO
Project description:BackgroundIn animals, signaling of Bone Morphogenetic Proteins (BMPs) is essential for dorsoventral (DV) patterning of the embryo, but how BMP signaling evolved with changes in embryonic DV differentiation is largely unclear. Based on the extensive knowledge of BMP signaling in Drosophila melanogaster, the morphological diversity of extraembryonic tissues in different fly species provides a comparative system to address this question. The closest relatives of D. melanogaster with clearly distinct DV differentiation are hover flies (Diptera: Syrphidae). The syrphid Episyrphus balteatus is a commercial bio-agent against aphids and has been established as a model organism for developmental studies and chemical ecology. The dorsal blastoderm of E. balteatus gives rise to two extraembryonic tissues (serosa and amnion), whereas in D. melanogaster, the dorsal blastoderm differentiates into a single extraembryonic epithelium (amnioserosa). Recent studies indicate that several BMP signaling components of D. melanogaster, including the BMP ligand Screw (Scw) and other extracellular regulators, evolved in the dipteran lineage through gene duplication and functional divergence. These findings raise the question of whether the complement of BMP signaling components changed with the origin of the amnioserosa.ResultsTo search for BMP signaling components in E. balteatus, we generated and analyzed transcriptomes of freshly laid eggs (0-30 minutes) and late blastoderm to early germband extension stages (3-6 hours) using Roche/454 sequencing. We identified putative E. balteatus orthologues of 43% of all annotated D. melanogaster genes, including the genes of all BMP ligands and other BMP signaling components.ConclusionThe diversification of several BMP signaling components in the dipteran linage of D. melanogaster preceded the origin of the amnioserosa.[Transcriptome sequence data from this study have been deposited at the NCBI Sequence Read Archive (SRP005289); individually assembled sequences have been deposited at GenBank (JN006969-JN006986).].
| S-EPMC3224130 | biostudies-literature
Project description:The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. Mutations in the BMP receptor ACVR1 cause the rare genetic disease fibrodysplasia ossificans progressiva (FOP) in which extensive and progressive extra-skeletal bone forms in soft connective tissues after birth. These mutations, which enhance BMP-pSmad1/5 pathway activity to induce ectopic bone, also affect skeletal development. FOP can be diagnosed at birth by symmetric, characteristic malformations of the great toes (first digits) that are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. To elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, we used an Acvr1R206H/+;Prrx1-Cre knock-in mouse model that mimics the first digit phenotype of human FOP. We have determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, Gdf5+ joint progenitor cell localization, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP.
| S-EPMC8035973 | biostudies-literature
Project description:Skeletal myogenesis is a regulated process in which mononucleated cells, the myoblasts, undergo proliferation and differentiation. Upon differentiation, the cells align with each other, and subsequently fuse to form terminally differentiated multinucleated myotubes. Previous reports have identified the protein osteoglycin (Ogn) as an important component of the skeletal muscle secretome, which is expressed differentially during muscle development. However, the posttranscriptional regulation of Ogn by microRNAs during myogenesis is unknown. Bioinformatic analysis showed that miR-155 potentially targeted the Ogn transcript at the 3´-untranslated region (3´ UTR). In this study, we tested the hypothesis that miR-155 inhibits the expression of the Ogn to regulate skeletal myogenesis. C2C12 myoblast cells were cultured and miR-155 overexpression or Ogn knockdown was induced by transfection with miR-155 mimic, siRNA-Ogn, and negative controls with lipofectamine for 15 hours. Near confluence (80-90%), myoblasts were induced to differentiate myotubes in a differentiation medium. Luciferase assay was used to confirm the interaction between miR-155 and Ogn 3'UTR. RT-qPCR and Western blot analyses were used to confirm that the differential expression of miR-155 correlates with the differential expression of myogenic molecular markers (Myh2, MyoD, and MyoG) and inhibits Ogn protein and gene expression in myoblasts and myotubes. Myoblast migration and proliferation were assessed using Wound Healing and MTT assays. Our results show that miR-155 interacts with the 3'UTR Ogn region and decrease the levels of Ogn in myotubes. The overexpression of miR-155 increased MyoG expression, decreased myoblasts wound closure rate, and decreased Myh2 expression in myotubes. Moreover, Ogn knockdown reduced the expression levels of MyoD, MyoG, and Myh2 in myotubes. These results reveal a novel pathway in which miR-155 inhibits Ogn expression to regulate proliferation and differentiation of C2C12 myoblast cells.
| S-EPMC5697837 | biostudies-literature
Project description:BackgroundTyrosine kinase inhibitors (TKIs) are effective therapies with demonstrated antineoplastic activity. Nilotinib is a second-generation FDA-approved TKI designed to overcome Imatinib resistance and intolerance in patients with chronic myelogenous leukemia (CML). Interestingly, TKIs have also been shown to be an efficient treatment for several non-malignant disorders such fibrotic diseases, including those affecting skeletal muscles.MethodsWe investigated the role of Nilotinib on skeletal myogenesis using the well-established C2C12 myoblast cell line. We evaluated the impact of Nilotinib during the time course of skeletal myogenesis. We compared the effect of Nilotinib with the well-known p38 MAPK inhibitor SB203580. MEK1/2 UO126 and PI3K/AKT LY294002 inhibitors were used to identify the signaling pathways involved in Nilotinib-related effects on myoblast. Adult primary myoblasts were also used to corroborate the inhibition of myoblasts fusion and myotube-nuclei positioning by Nilotinib.ResultsWe found that Nilotinib inhibited myogenic differentiation, reducing the number of myogenin-positive myoblasts and decreasing myogenin and MyoD expression. Furthermore, Nilotinib-mediated anti-myogenic effects impair myotube formation, myosin heavy chain expression, and compromise myotube-nuclei positioning. In addition, we found that p38 MAPK is a new off-target protein of Nilotinib, which causes inhibition of p38 phosphorylation in a similar manner as the well-characterized p38 inhibitor SB203580. Nilotinib induces the activation of ERK1/2 and AKT on myoblasts but not in myotubes. We also found that Nilotinib stimulates myoblast proliferation, a process dependent on ERK1/2 and AKT activation.ConclusionsOur findings suggest that Nilotinib may have important negative effects on muscle homeostasis, inhibiting myogenic differentiation but stimulating myoblasts proliferation. Additionally, we found that Nilotinib stimulates the activation of ERK1/2 and AKT. On the other hand, we suggest that p38 MAPK is a new off-target of Nilotinib. Thus, there is a necessity for future studies to investigate the long-term effects of TKIs on skeletal muscle homeostasis, along with potential detrimental effects in cell differentiation and proliferation in patients receiving TKI therapies.
| S-EPMC5819301 | biostudies-literature