Mus musculus
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ABSTRACT:
PROVIDER: PRJNA376517 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle has an impressive ability to repair itself after a damaging insult and this response is essential to the process of muscle adaptation. In conditions such as muscular dystrophy and the sarcopenia of old age, repair is compromised leading to fibrosis and fatty tissue accumulation. Hypoxia-inducible factors (HIFs) are highly conserved regulators of gene transcription under conditions of low oxygen tension and HIF target genes such as EPO and VEGF have been associated with muscle protection and repair. We sought to interrogate the importance of HIF activation to skeletal muscle repair through the use of prolyl hydroxylase inhibitors (PHI) that stabilize HIF and activate target gene transcription in a mouse eccentric exercise limb damage model. We used microarrays to detail the global effects of prolyl hydroxylase inhibitors (PHI) in a mouse eccentric exercise limb damage model.
2017-08-23 | GSE95244 | GEO
Project description:Common acute injuries to skeletal muscle can lead to significant pain and disability. The current therapeutic approaches for treating muscle injuries are dependent on the clinical severity but not on the type of injury. The aim of this study was to compare the molecular events accompanying the degeneration and repair phases of contraction- and trauma-induced muscle injuries by applying DNA microarray methodology to two well-characterized mouse models of skeletal muscle injury, i.e., eccentric contraction-induced injury (CI) and traumatic injury induced by freezing (FI). Histopathological evaluation and measurements of muscle strength were accompanied by analyses of expression for 12,488 known genes at four time points ranging from 6 hours to 7 days post-injury. Real-time RT-PCR was used to confirm some of the gene expression temporal profiles. While both types of injury cause early induction of transcription, myogenic, and stress-responsive factors, they also induce injury type-specific gene expression profiles. CI only activates a set of genes associated with the protection and repair of protein and structural integrity while FI activates gene sets which result in extensive inflammatory responses, tissue remodeling, angiogenesis, and myofibre and extracellular matrix synthesis. This study identified genes that are candidates for therapeutic manipulation following two disparate types of muscle injury. Experiment Overall Design: 2 types of skeletal muscle injury (eccentric contraction- and freeze-induced) x 4 time points after injury (6 hours, 1 day, 3 days, and 7 days post-injury). There were 3 samples for each of the 8 cells with the exception of the 'contraction injury, 1 day post-injury' and 'freeze injury, 7 days post-injury' cells; for each of these 2 cells, there were only 2 samples. Additionally, there were 3 control (i.e., uninjured) muscle samples.
2007-11-22 | E-GEOD-5413 | biostudies-arrayexpress
Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an /-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIF levels and FIH catalysis regulates HIF activity. How differences in HIF hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.
2016-10-25 | E-MTAB-4264 | biostudies-arrayexpress
Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an α/β-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIFα levels and FIH catalysis regulates HIF activity. How differences in HIFα hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.
2016-08-31 | E-MTAB-4300 | biostudies-arrayexpress
Project description:Mammalian kidney has very limited ability to repair or regenerate after acute kidney injury (AKI). The maladaptive repair of AKI promotes the progression to chronic kidney disease (CKD). Therefore, it is extremely urgent to explore new strategies to promote the repair/regeneration of injured renal tubules after AKI. It has been shown that hypoxia induces heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxia condition and found that MK-8617 significantly ameliorates ischemia reperfusion injury (IRI) induced acute kidney injury. We then showed that MK-8617 dramatically facilitates renal regeneration via promoting the proliferation of injured renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis- related genes were significantly upregulated with MK-8617 pretreatment. Furthermore, we showed that MK-8617 may alleviate proximal tubule injury via stabilizing HIF-1α protein specifically in renal proximal tubular cells. We also demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells, and the regeneration of renal proximal tubules. In summary, we discovered that inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI via promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.
2024-10-10 | GSE247560 | GEO
Project description:Background: Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Methods: Utilizing the NPDA/B mouse model ASM−/− and wild type (WT) littermates, we performed excitation- contraction coupling/Ca2+ mobilization and sarcolemma injury/repair assays with isolated flexor digitorum brevis fibers, proteomic analyses with quadriceps femoris, flexor digitorum brevis, and tibialis posterior muscle and in vivo tests of the contractile force (maximal isometric torque) of the quadriceps femoris muscle before and after eccentric contraction-induced muscle injury. Results: ASM−/− flexor digitorum brevis fibers showed impaired excitation-contraction coupling compared to WT, a defect expressed as reduced tetanic [Ca2+]i in response to electrical stimulation and early failure in sustaining [Ca2+]i during repeated tetanic contractions. When injured mechanically by needle passage, ASM−/− flexor digitorum brevis fibers showed susceptibility to injury similar to WT, but a reduced ability to reseal the sarcolemma. Proteomic analyses revealed changes in a small group of skeletal muscle proteins as a consequence of ASM deficiency, with downregulation of calsequestrin occurring in the three different muscles analyzed. In vivo, the loss in maximal isometric torque of WT quadriceps femoris was similar immediately after and 2 min after injury. The loss in ASM−/− mice immediately after injury was similar to WT, but was markedly larger at 2 min after injury. Conclusions: Skeletal muscle fibers from ASM−/− mice have an impairment in intracellular Ca2+ handling that results in reduced Ca2+ mobilization and a more rapid decline in peak Ca2+ transients during repeated contraction-relaxation cycles. Isolated fibers show reduced ability to repair damage to the sarcolemma, and this is associated with an exaggerated deficit in force during recovery from an in vivo eccentric contraction- induced muscle injury. Our findings uncover the possibility that skeletal muscle functional defects may play a role in the pathology of NPDA/B disease.
2023-06-28 | PXD019356 | Pride
Project description:RNA sequencing of primary human monocytes cultured with and without hypoxia-mimetic agent DMOG (Dimethyloxalylglycine). Monocytes isolated from PBMCs of 7 healthy donors were cultured with and without DMOG for 24hrs and harvested at 0, 2, 10 or 24hrs for RNA sequencing. DMOG suppresses HIF Prolyl hydroxylase (HIF-PH) activity by acting as a small molecule competitive inhibitor. HIF-PH inhibition leads to increase in endogenous HIF protein levels and mimics aspects of hypoxia. This RNA-seq study allows analysis of transciptome-wide expression pattern changes over time due to DMOG treatment.
2022-04-13 | GSE165998 | GEO
Project description:ATAC sequencing of primary human monocytes cultured with and without hypoxia-mimetic agent DMOG (Dimethyloxalylglycine). Monocytes isolated from PBMCs of 7 healthy donors were cultured with and without DMOG for 24hrs and harvested at 0, 2, 10 or 24hrs for RNA sequencing. DMOG suppresses HIF Prolyl hydroxylase (HIF-PH) activity by acting as a small molecule competitive inhibitor. HIF-PH inhibition leads to increase in endogenous HIF protein levels and mimics aspects of hypoxia. This ATAC-seq study allows analysis of genome-wide changes to chromatin accessibility due to DMOG treatment.
2022-04-13 | GSE165997 | GEO
Project description:Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects other organs at a distance. We developed mouse models to ask if inhibition of EglN1, which senses oxygen and regulates the HIF transcription factor, could suffice to mediate local and remote ischemic preconditioning. We used microarrays to detail the global expression changes induced when the oxygen sensor EglN1 is genetically deleted from skeletal muscle cells. We also used microarrays to assess the transcriptome alterations that occur in mouse hearts with pharmacologic inhibition of EglN1, using the EglN inhibitor FG-4497. We generated mice with a tamoxifen-inducible model of EglN1 loss using a floxxed EglN1 locus with skeletal muscle-specific CRE recombinase. WT mice and mice with the floxxed EglN1 locus were exposed to tamoxifen. Mouse skeletal muscle was isolated for RNA extraction and hybridization on Affymetrix microarrays. In a related experiment, mice were treated with the EglN inhibitor FG-4497, and RNA from their heart tissue was analyzed by microarray for transcriptome alterations compared to control hearts.
2016-02-11 | E-GEOD-77789 | biostudies-arrayexpress
Project description:Common acute injuries to skeletal muscle can lead to significant pain and disability. The current therapeutic approaches for treating muscle injuries are dependent on the clinical severity but not on the type of injury. The aim of this study was to compare the molecular events accompanying the degeneration and repair phases of contraction- and trauma-induced muscle injuries by applying DNA microarray methodology to two well-characterized mouse models of skeletal muscle injury, i.e., eccentric contraction-induced injury (CI) and traumatic injury induced by freezing (FI). Histopathological evaluation and measurements of muscle strength were accompanied by analyses of expression for 12,488 known genes at four time points ranging from 6 hours to 7 days post-injury. Real-time RT-PCR was used to confirm some of the gene expression temporal profiles. While both types of injury cause early induction of transcription, myogenic, and stress-responsive factors, they also induce injury type-specific gene expression profiles. CI only activates a set of genes associated with the protection and repair of protein and structural integrity while FI activates gene sets which result in extensive inflammatory responses, tissue remodeling, angiogenesis, and myofibre and extracellular matrix synthesis. This study identified genes that are candidates for therapeutic manipulation following two disparate types of muscle injury. Keywords: time course, comparative genomic hybridization
2006-12-31 | GSE5413 | GEO