Non-cell Autonomous Mechanisms Control Mitochondrial Gene Dysregulation in Polycystic Ovary Syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE188740 | GEO | 2022/01/10
REPOSITORIES: GEO
Similar Datasets
Project description:Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive-aged women. Exercise is often recommended as a first-line therapy for women with PCOS to help improve their overall health however, women with PCOS are resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether muscle cells from women with PCOS have an altered gene expression signature in response to muscle contraction. Following EPS, 4,719 genes were differentially expressed (FDR < 0.05) in myotubes from women with PCOS compared to only 173 in healthy control women. Both groups included genes involved in skeletal muscle contraction. We also determined the effect of two transforming growth factor-beta ligands that are elevated in plasma of women with PCOS, the transforming growth factor beta-1 (TGFβ1) and the anti-müllerian hormone (AMH), alone and on the EPS-induced response. While AMH (30 ng/ml) had no effect, TGFβ1 (5 ng/ml) induced the expression of extracellular matrix genes and impaired the exercise-like gene expression signature in myotubes from women with and without PCOS in response to EPS by interfering with key processes related to muscle contraction, calcium transport and actin filament. Collectively, our findings suggest that while the fundamental gene expression responses of skeletal muscle to contraction is intact in PCOS, elevated circulating factors like TGFβ1 may be responsible for the impaired adaptation to exercise intervention in women with PCOS.
2022-10-12 | GSE199225 | GEO
Project description:To explore the molecular mechanisms of obesity and insulin resistance in the patients with polycystic ovary syndrome (PCOS) at the level of human embryonic stem cells (hESCs).Three PCOS-derived and one non-PCOS-derived hESC lines were induced into adipocytes, and then total mRNA was extracted from these adipocytes. The differential genes between PCOS-derived and non-PCOS-derived adipocytes were identified with GeneChip, and then were validated with real-time PCR.There were 153 differential genes. Of the 153 genes, 91 genes were up-regulated and 62 down-regulated. Nuclear receptor subfamily 0, group B, member 2 (NR0B2) was an up-regulated gene, and GeneChip software system indicated that it was associated with obesity and diabetes. Three PCOS-derived and one non-PCOS-derived hESC lines were induced into adipocytes, and then total mRNA was extracted from these adipocytes. The differential genes between PCOS-derived and non-PCOS-derived adipocytes were identified with GeneChip, and then were validated with real-time PCR.
2013-11-22 | E-GEOD-52422 | biostudies-arrayexpress
Project description:Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women resulting in ovulation failure and other metabolic problems. However, the underlying mechanisms of it remain largely uncertain due to its complexity of clinical manifestations. Since PCOS is believed as a systemic disorder involved endocrine, metabolism, immune system and many organs, we therefore want to know what happen in the peripheral blood of patients with PCOS. To this purpose, gene expression patterns of peripheral blood from 10 PCOS patients and 10 healthy women were profiled by microarray. The significance analysis of microarray (SAM) software was employed to screen the differentially expressed genes (DEGs) and gene ontology (GO) was used for functional enrichment analysis. Also, quantitative reverse-transcription PCR (qRT-PCR) was performed to confirm the results from microarray. 181 DEGs with a fold change >2.0 and q-value <0.05 were identified between the groups. Of these genes, 149 were up-regulated and 32 down-regulated in PCOS. Importantly, 14 genes associated with inflammatory response pathway were highly enriched in PCOS. Furthermore, qPCR assays validated the dysregulated inflammatory response genes. Our observation reinforces the hypothesis that PCOS is characterized by the presence of systemic inflammatory changes and inflammation is implicated in the pathogenesis of this entity. Further elucidation of the aberrant expression of inflammation-related genes how to affect the pathogenesis of PCOS may lead to the development of novel preventative and therapeutic strategies.
2017-01-01 | GSE85932 | GEO
Project description: Not available
| S-EPMC8679849 | biostudies-literature
Project description:Skeletal muscle atrophy is dictated by the balance between protein synthesis and protein breakdown, known as proteostasis. With advanced age, muscle atrophy contributes to development of co-morbidities, loss of strength and independence, and all-cause mortality. Aging also coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence associated secretory phenotype. Previously, we found that a metformin + leucine (MET+LEU) combination treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the objective of this study was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during serum-deprivation (SD) atrophy. Single myofibers were isolated from aged (22-23 mo) C57Bl6/J mice, and human primary myoblasts were extracted from a healthy older adult donor. 25 + 125 µM MET+LEU treatment increased differentiation of myotubes and prevented SD induced atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent myotube atrophy and cause transcriptional reprogramming compared to individual therapies. SD increased inflammatory and cellular senescence pathways that was reversed with MET+LEU treatment. SD resulted in dysregulated proteostasis that was rescued with MET+LEU, and proteasome inhibition with MG-132 also rescued myotube atrophy. Cellular senescence transcriptional pathways and markers increased by SD were reversed with MET+LEU treatment, and dasatinib + quercetin (D+Q) senolytic treatment prevented myotube atrophy similar to MET+LEU. In aged myofibers, MET+LEU prevented SD atrophy, and in human primary myotubes MET+LEU prevented reductions in myonuclei fusion. These data provide evidence that MET+LEU has muscle cell intrinsic properties to prevent atrophy by reversing senescence and improving proteostasis
2023-04-19 | GSE221941 | GEO
Project description:Muscle spindles are skeletal muscle stretch receptors that mediate axial and limb position sensation (proprioception) to the central nervous system. Defective proprioception, often characterized by gait ataxia and poor coordination, is present in a variety of human sensory and motor neuropathies having diverse etiologies. Spindles contain specialized intrafusal muscle fibers that are induced during development by sensory innervation. The molecular events mediating the morphogenetic induction process are poorly characterized but depend upon neuregulins and their cognate ErbB receptor signaling. Recently, we demonstrated that the transcription factor Egr3 is induced and regulated by intrafusal muscle fiber sensory innervation during spindle induction. Moreover, Egr3-deficient mice have impaired spindle morphogenesis and profound gait ataxia. Thus, Egr3 mediated transcription is critical for muscle stretch receptor development and potentially for myotube fate specification.,Egr3 may mediate spindle morphogenesis induced by Neuregulin/ErbB signaling after myotubes are contacted by sensory axons during development. As a starting point for understanding the specific role for Egr3 in this process, we will use a genome wide expression analysis to identify genes regulated (either directly or indirectly) by Egr3 in primary myotubes. It is not practical to examine Egr3 mediated gene expression directly within spindles since they comprise less than 0.1% of the muscle mass. Therefore, gene expression analysis will be examined in primary myotubes grown in vitro. Primary myoblasts isolated from mice and differentiated in vitro are biochemically most similar to extrafusal muscle fibers which do not express Egr3. To identify genes regulated by Egr3 in myotubes, gene expression in myotubes enforced to express full length Egr3 will be compared to gene expression in myotubes enforced to express truncated (transcriptionally inactive) Egr3.,Egr3-deficient mice lack muscle spindles and have profound proprioceptive deficits. Egr3 is specifically expressed in a subset of developing primary myotubes after innervation by sensory axons. Spindle induction is dependent upon sensory/myotube contact which involves sensory axon produced neuregulin and ErbB receptor signaling in the myotube. Shortly after or during induction, Egr3 expression is upregulated and maintained in the nascent myotube/spindle as one of the earliest molecular events know to occur during spindle morphogenesis. We hypothesize that Egr3 mediated transcription is critical for engaging gene programs specific to and essential for, muscle spindle formation. Moreover, Egr3 may be involved in fate specification of myotubes that develop into biochemically and physiologically distinct intrafusal muscle fibers within spindles. To date, the target genes regulated by Egr3 during spindle morphogenesis have not been characterized.,Myoblasts from wild type newborn mice will be isolated and purified. Myoblasts will be plated on collagen coated plates and differentiated in vitro for 7 days. During in vitro differentiation, myoblasts fuse to form multinucleated myotubes that exhibit contractile properties. Egr3 is not expressed in myotubes in vitro, which is consistent with their similarity to extrafusal muscle fibers that also do not express Egr3 in vivo. Only intrafusal fibers of muscle spindles express high levels of Egr3 in this muscle fiber context. Adenoviruses that express full length Egr3 (Egr3wt; transcriptionally active) and truncated Egr3 (Egr3tr; transcriptionally inactive) have been generated and characterized in our laboratory. After 7 days of in vitro differentiation, primary myotubes will be infected with either Egr3wt or Egr3tr adenoviruses. 100% infection is routinely obtained which is confirmed by coexpression of enhanced green fluorescent protein (EGFP). Care will be taken to minimize viral induced toxicity of the myotubes after infection. Myotubes are maintained after infection for 24 hours, after which total RNA is extracted from the cell lysates. The two RNA samples will be used for microarray analysis to identify genes that are upregulated and downregulated by Egr3 in the myotube cellular context. We will repeat the infection, RNA isolation and microarray analysis three times to minimize identifying false positive differentially expressed genes. Differentially expressed genes will be confirmed using real-time PCR. Interesting differentially expressed genes will be examined by in situ hybridization to determine if they are specifically expressed in wild type spindles. Since the identified differentially expressed genes will represent both indirect and direct target genes, we will perform Chromatin Immunoprecipitation (ChIP) from Egr3wt infected myotubes and screen the ChIP DNA library by PCR to determine which gene promoters are directly bound by Egr3.
2007-07-07 | E-GEOD-1998 | biostudies-arrayexpress
Project description:Enhancing the proliferation and myogenic commitment of progenitor cells during fetal development enhances muscle growth and lean production in offspring. During the early development, a pool of skeletal stem cells (SSCs) proliferates and then diverge into either myoblast. Myoblast further fusion and develop into myotube. However, the landscape from muscle stem cells to myotubes in goats is not yet clear. This study aims to characterize the changes in the expression profile of skeletal muscle stem cells that differentiate into myoblasts, then migrate and fuse to form myotubes.
2021-11-11 | PXD029693 | iProX
Project description:To explore the molecular mechanisms of obesity and insulin resistance in the patients with polycystic ovary syndrome (PCOS) at the level of human embryonic stem cells (hESCs).Three PCOS-derived and one non-PCOS-derived hESC lines were induced into adipocytes, and then total mRNA was extracted from these adipocytes. The differential genes between PCOS-derived and non-PCOS-derived adipocytes were identified with GeneChip, and then were validated with real-time PCR.There were 153 differential genes. Of the 153 genes, 91 genes were up-regulated and 62 down-regulated. Nuclear receptor subfamily 0, group B, member 2 (NR0B2) was an up-regulated gene, and GeneChip software system indicated that it was associated with obesity and diabetes.
2013-11-22 | GSE52422 | GEO
Project description:Analysis of gene expression profile of Tibialis anterior (TA) skeletal muscle tissues with Notch1 intracellular domain (N1ICD) overexpression. Skeletal myogenesis involves sequential activation, proliferation, self-renewal/differentiation and fusion of myogenic stem cells (satellite cells). Notch signaling is known to be essential for the maintenance of satellite cells, but its function in late-stage myogenesis, i.e. post-differentiation myocytes and post-fusion myotubes, is unknown. Here we use muscle creatine kinase (MCK)-Cre to induce N1ICD expression in multinucleated myotubes. We found that myotube-specific Notch1 activation improved muscle regeneration and exercise performance of mdx mice, a model of Duchenne Muscular Dystrophy (DMD). Agilent microarray was performed to compare gene expression in mdx control and N1ICD-overexpressing mdx muscles. The results may provide mechanistic insights into how Notch1 activation in myotubes modulate muscle function.
2016-10-01 | GSE81242 | GEO
Project description:Aberration in miRNA expression or DNA methylation is a causal factor for numerous pathological conditions including polycystic ovarian syndrome PCOS, a common endocrine disorders and leading cause of infertility. The epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. Our study identifies epigenetic alternation in ovarian granulosa cells from PCOS patients and helps to reveal the pathogenesis of PCOS.
2019-10-09 | GSE138573 | GEO