In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Carsten Sticht
PROVIDER: E-GEOD-36745 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:In the present study, we used a multimodal approach including protein and gene expression analysis and combined in vivo and in vitro measurements of force production. Overall, we aimed at investigating the functional impact of the expression of a single nebulin allele. Comparison of the miRNA expression profile of quadriceps in 3 nebulin wild type mice with 3 nebulin heterozygous mice.
2012-09-01 | E-GEOD-36741 | biostudies-arrayexpress
Project description:In the present study, we used a multimodal approach including protein and gene expression analysis and combined in vivo and in vitro measurements of force production. Overall, we aimed at investigating the functional impact of the expression of a single nebulin allele. Comparison of the mRNA expression profile of quadriceps in 3 nebulin wild type mice with 3 nebulin heterozygous mice.
2012-09-01 | E-GEOD-36743 | biostudies-arrayexpress
Project description:In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [miRNA]
| PRJNA155437 | ENA
Project description:In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [mRNA]
| PRJNA155441 | ENA
Project description:Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical NEM adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin’s functional roles in adult muscle we performed studies on a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscle but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survives to adulthood with low nebulin levels (<5% of control), contain nemaline rods, and undergo fiber-type switching towards oxidative types. These microarrays investigate the changes in gene expression when nebulin is deficient.
2015-06-25 | GSE70213 | GEO
Project description:Over-expression of wild type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. In this study we used DNA microarrays to identify 1499 transcripts that are temporally deregulated concomitant with inducible PrPC over-expression in the skeletal muscles of transgenic mice. Examination using microarrays revealed a transcriptional profile with both similarities and differences to previously investigated models of myopathies. Down-regulation of genes coding for the myofibrillar proteins MYH2, MYH6, MYH7, MYL2, MYL3 and up-regulation of lysosomal genes CTSS, CTSD, CTSZ, DPEP2, HEXA, HEXB and LAMP1 coincide with the observed myopathy and lysosome accumulation on over-expression of PrPC. Down-regulation of the MEF2C gene, a key regulatory transcriptional factor muscle development and remodeling of adult muscles in response to physiologic and pathologic signals, may contribute to the centrally placed nuclei in the skeletal muscles. Significantly, up-regulation of genes involved in p53 signaling and the induction of p53 protein, suggest a central role for this molecule in the myopathy. Several p53-regulated genes involved in cell cycle arrest (CDNK1A, GADD45a and GADD45b) and apoptosis (BAK1, PMAIP1, BBC3, and BAX) are induced. We suggest that PrPC over-expression in skeletal muscles, possibly in response to accumulation of a cytotoxic truncated form of PrP, causes a primary myopathy involving the induction of p53-dependent pathways. Wild type (WT), PrP-null (KO), and Tg(HQK) mice were fed food pellets either lacking or containing 6g doxycycline (Dox)/kg food to induce PrPC expression. Skeletal muscles from the quadriceps of hind legs were removed at day 0, 4, 7, 14, 30 and 60 days following administration of Dox. Total RNA was isolated from these tissues for use in subsequent microarray analysis. Mouse gene expression was analysed by two-colour microarray experiments using an inhouse manufactured 16K mouse cDNA microarray. Age matched reference mice (WT) and experimental (KO and HQK) Alexa Flour labeled aRNA were used in each competitive hybridization. Each sample was labeled individually with both Alexa Fluor 555 and 647 for subsequent dye-swapped hybridizations to account for intensity bias. 3 individual mice from each experimental group at each time point were individually processed for separate microarrays. We used the program EDGE to identify genes that were differentially expressed in mouse skeletal muscle in either transgenic HQK mice over expressing PrP, or PrP knock out (KO) mice after administration of Dox. We used a P value cut-off of 0.05 as the criteria of selection of significantly differentially expressed genes.
2008-08-27 | E-GEOD-12576 | biostudies-arrayexpress
Project description:Myopathies and muscular dystrophies are devastating diseases sharing characteristic symp-toms. Little is known about common aetiopathology and biomarkers are rare. We studied skeletal muscle gene expression in mouse models of myopathies. As dystrophic processes in muscles are characterised by inflammatory processes, we expanded our analy-sis on a rat model of sepsis. We find 25 commonly dysregulated genes. Sarcolipin was upregulated most, exhibiting in-creased protein levels in different muscles as well as in rats treated with an inflammatory agent. Upregulation strongly correlated with disease status. Our findings suggest Sarcolipin as a potential biomarker and imply a new function in inflam-matory response. Comparison of the expression profile of quadriceps in 2 B6C3Fe a/a-Ttnmdm/J mice with Titin-mutation versus the expression profile of 2 mice without the mutation in Titin [Ttn].
2011-12-09 | E-GEOD-33157 | biostudies-arrayexpress
Project description:Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical NEM adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin’s functional roles in adult muscle we performed studies on a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscle but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survives to adulthood with low nebulin levels (<5% of control), contain nemaline rods, and undergo fiber-type switching towards oxidative types. These microarrays investigate the changes in gene expression when nebulin is deficient. Two skeletal muscle groups were studied: Quadriceps (which is markedly smaller in the Neb cKO mice relative to control) and Soleus (which is not significantly smaller in the Neb cKO relative to control). Six biological replicates for each muscle group were selected; all are age-matched males.
2015-06-25 | E-GEOD-70213 | biostudies-arrayexpress
Project description:Maintenance of muscle function requires assembly of contractile proteins into highly organized sarcomeres. Mutations in Kelch-like protein 41 (KLHL41) cause nemaline myopathy, a fatal muscle disorder associated with sarcomere disarray. We generated KLHL41 mutant mice, which display lethal disruption of sarcomeres and aberrant expression of muscle structural and contractile proteins, mimicking the hallmarks of the human disease. We show that KLHL41 is poly-ubiquitinated and acts, at least in part, by preventing aggregation and degradation of nebulin, an essential component of the sarcomere. Furthermore, inhibition of KLHL41 poly-ubiquitination prevents its stabilization of nebulin, suggesting a unique role for ubiquitination in protein stabilization. These findings provide new insights into the molecular etiology of nemaline myopathy and reveal a mechanism whereby KLHL41 stabilizes sarcomeres and maintains muscle function by acting as a molecular chaperone. Similar mechanisms for protein stabilization likely contribute to the actions of other Kelch proteins.
2017-09-06 | GSE95543 | GEO