Loss of function of myosin chaperones triggers Hsf1-mediated transcriptional response in skeletal muscle cells
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE74202 | GEO | 2015/10/30
SECONDARY ACCESSION(S): PRJNA299318
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptional analysis of zebrafish embryos and larvae from wild type and muscles mutants Biological samples sequenced in duplicates
2015-10-30 | E-GEOD-74202 | biostudies-arrayexpress
Project description:BackgroundMutations in myosin chaperones Unc45b and Hsp90aa1.1 as well as in the Unc45b-binding protein Smyd1b impair formation of myofibrils in skeletal muscle and lead to the accumulation of misfolded myosin. The concomitant transcriptional response involves up-regulation of the three genes encoding these proteins, as well as genes involved in muscle development. The transcriptional up-regulation of unc45b, hsp90aa1.1 and smyd1b is specific to zebrafish mutants with myosin folding defects, and is not triggered in other zebrafish myopathy models.ResultsBy dissecting the promoter of unc45b, we identify a Heat shock factor 1 (Hsf1) binding element as a mediator of unc45b up-regulation in myofibers lacking myosin folding proteins. Loss-of-function of Hsf1 abolishes unc45b up-regulation in mutants with defects in myosin folding.ConclusionsTaken together, our data show that skeletal muscle cells respond to defective myosin chaperones with a complex gene program and suggest that this response is mediated by Hsf1 activation.
| S-EPMC4668643 | biostudies-literature
Project description:Fast skeletal myosin binding protein-C (fMyBP-C) is one of three MyBP-C paralogs and is predominantly expressed in fast skeletal muscle. Mutations in the gene that encodes fMyBP-C, MYBPC2, is associated with distal arthrogryposis, while fMyBP-C protein is reduced in diseased muscle. However, the functional and structural roles of fMyBP-C in skeletal muscle remain unclear. To address this gap, we generated a homozygous fMyBP-C knockout mouse (C2-/-) and characterized it, both in vivo and in vitro. Ablation of fMyBP-C was benign in terms of muscle weight, fiber type, cross-sectional area, and sarcomere ultrastructure. However, grip strength and plantar-flexor muscle strength were significantly decreased in C2-/- compared to WT. Peak isometric tetanic force (Po) and isotonic speed of contraction were significantly reduced in isolated extensor digitorum longus (EDL) from C2-/- mice. In EDL muscles of C2-/- mice, small-angle X-ray diffraction revealed significant increase in equatorial intensity ratio (I1.1/I1.0) during contraction, indicating a greater degree of myosin head shift towards actin while MLL4 layer-line intensity was decreased at rest, indicating less ordered myosin heads at rest. Interfilament lattice spacing was also significantly increased in C2-/- EDL muscle compared to WT. Consistent with these findings, we observed a significant reduction of steady-state isometric force during Ca2+ activations, myofilament calcium sensitivity, sinusoidal stiffness in skinned EDL muscle fibers from C2-/- mice. Finally, C2-/- muscles displayed disruption of inflammatory and regenerative genes and increased muscle damage upon mechanical overload. Together, our data suggest that fMyBP-C is essential for maximal speed and force of contraction, sarcomere integrity, and calcium sensitivity in fast twitch muscle.
2020-11-30 | GSE160827 | GEO
Project description:mRNA from 4 different muscles from control and Myosin heavy chain-embryonic knockout neonate mice were sequenced.
2020-03-08 | GSE100331 | GEO
Project description:To understand the underlying cause of the swimming defect in Cavin4/Murcb deficient larvae, we isolated mRNA from mutant and sibling zebrafish at 72 hpf and subjected it to microarray analysis. RNA and gDNA were extracted from individual larvae at 72 hpf using Trizol (Life Technologies). Following genotyping, the aqueous phases from at least 10 Trizol extractions were combined by genotype and purified over microspin columns (ZymoResearch). RNA expression from heterozygous and mutant larvae was analyzed by single-color microarray (8x60K Zebrafish Array XS, Oaklabs, Germany).
2015-07-14 | E-GEOD-70858 | biostudies-arrayexpress
Project description:Single-cell RNA-sequencing (scRNA-seq) was applied to identify and characterise macrophage subsets that responded to larval zebrafish muscle injury. The Tg(mpeg1:mCherry) transgenic zebrafish line was utilised to isolate mCherry-expressing macrophages by FACS. Following needle-stab muscle injury of a 4 days post fertilisation (dpf) larvae, the wound site was dissected out at 1, 2, and 3 days post injury (dpi) for macrophage isolation. Macrophages isolated from 4 dpf-uninjured larvae were also included. This analysis led to the identification of 8 discrete clusters of macrophages, one of which corresponded to uninjured macrophages. The 7 wound-present macrophage subsets highlighted greater macrophage heterogeneity than previously described in an in vivo skeletal muscle injury context.
2020-12-11 | GSE162979 | GEO
Project description:To understand the underlying cause of the swimming defect in Cavin4/Murcb deficient larvae, we isolated mRNA from mutant and sibling zebrafish at 72 hpf and subjected it to microarray analysis.
2015-07-14 | GSE70858 | GEO
Project description:The folding and assembly of myosin motor proteins is essential for most movement processes at the cellular, but also at the organism level. Importantly, myosins, which represent a very diverse family of proteins, require the activity of general and specialized folding factors to develop their full motor function. The activities of the myosin-specific UCS (UNC-45/Cro1/She4) chaperones range from assisting acto-myosin dependent transport processes to scaffolding multi-subunit chaperone complexes, which are required to assemble myofilaments. Recent structure-function studies revealed the structural organization of TPR (tetratricopeptide repeat)-containing and TPR-less UCS chaperones. The observed structural differences seem to reflect the specialized and remarkably versatile working mechanisms of myosin-directed chaperones, as will be discussed in this review.
| S-EPMC4045384 | biostudies-literature
Project description:Acute exposure to acrylamide (ACR), a type-2 alkene, may lead to a ataxia, skeletal muscles weakness and numbness of the extremities in exposed human and laboratory animals. Recently, a zebrafish model for ACR neurotoxicity mimicking most of the pathophysiological processes described in mammalian models, was generated in 8 days post-fertilization larvae. In order to better understand the predictive value of the zebrafish larvae model of acute ACR neurotoxicity, in the present manuscript the ACR acute neurotoxicity has been characterized in the brain of adult zebrafish, and the results compared with those obtained with the whole-larvae. Although qualitative and quantitative analysis of the data shows important differences in the ACR effects between the adult brain and the whole-larvae, the overall effects of ACR in adult zebrafish, including a significant decrease in locomotor activity, altered expression of transcriptional markers of proteins involved in synaptic vesicle cycle, presence of ACR-adducts on cysteine residues of some synaptic proteins, and changes in the profile of some neurotransmitter systems, are similar to those described in the larvae. Thus, these results support the suitability of the zebrafish ACR acute neurotoxicity recently developed in larvae for screening of molecules with therapeutic value to treat this toxic neuropathy.
2018-10-19 | PXD008993 | Pride
Project description:BackgroundHeparin enhances the ability of the plasma protease inhibitor, antithrombin, to neutralize coagulation factor Xa and thrombin. Skeletal muscle myosin binds unfractionated heparin.ObjectivesThe aim of this study was to investigate the influence of myosin binding to heparin on antithrombin's anticoagulant activity.MethodsInhibition of factor Xa and thrombin by antithrombin in the presence of different heparins and skeletal muscle myosin or cardiac myosin was studied by measuring inhibition of each enzyme's chromogenic substrate hydrolysis.Results and conclusionsSkeletal muscle myosin and cardiac myosin neutralized unfractionated heparin's enhancement of antithrombin's inhibition of purified factor Xa and thrombin. Skeletal muscle myosin also reduced the inhibition of factor Xa and thrombin by antithrombin in the presence of heparan sulfate. These two myosins did not protect factor Xa from antithrombin inhibition when tested in the presence of smaller heparins (eg, low molecular weight heparin, heparin pentasaccharide). This chain length dependence for skeletal muscle myosin's ability to reduce heparin's anticoagulant activity might have potential implications for therapy for patients who experience increases in plasma myosin levels (eg, acute trauma patients). In addition to the chain length, the type and extent of sulfation of glycosaminoglycans influenced the ability of skeletal muscle myosin to neutralize the polysaccharide's ability to enhance antithrombin's activity. In summary, these studies show that skeletal muscle myosin and cardiac myosin can influence antithrombin's anticoagulant activity against factor Xa and thrombin, implying that they may significantly influence the hemostatic balance involving bleeding vs clotting.
| S-EPMC7902397 | biostudies-literature