Factors Associated with Induced Chronic Inflammation in mdx Skeletal Muscle Cause Posttranslational Stabilization and Augmentation of Extrasynaptic Sarcolemmal Utrophin

Waheed, Ishrat; Gilbert, Rénald; Nalbantoglu, Joséphine; Guibinga, Ghiabe H.; Petrof, Basil J.; Karpati, George

doi:10.1089/hum.2005.16.489

Cited by 16 publications

(9 citation statements)

References 70 publications

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“…This finding provides an explanation for the discrepancy between utrophin A protein and transcript levels observed in various studies. Although these findings do not exclude the possibility that post-translational mechanisms, such as alterations in protein stability, may also partially account for these discrepancies between protein and mRNA levels (25,27,64), our data add considerably to the growing literature highlighting the importance of translational control for the regulation of synaptic proteins in muscle and nerve. Additionally, our results provide an additional target from which pharmacological interventions may be rationally designed to stimulate utrophin A expression in muscle fibers from DMD patients in attempts to alter the progression of this neuromuscular disorder and provide functional benefits.…”

Section: Discussioncontrasting

confidence: 60%

The Utrophin A 5′-Untranslated Region Confers Internal Ribosome Entry Site-mediated Translational Control during Regeneration of Skeletal Muscle Fibers

Miura

Thompson

Chakkalakal

et al. 2005

Journal of Biological Chemistry

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Utrophin up-regulation in muscle fibers of Duchenne muscular dystrophy patients represents a potential therapeutic strategy. It is thus important to delineate the regulatory events presiding over utrophin in muscle in attempts to develop pharmacological interventions aimed at increasing utrophin expression. A number of studies have now shown that under several experimental conditions, the abundance of utrophin is increased without a corresponding elevation in its mRNA. Here, we examine whether utrophin expression is regulated at the translational level in regenerating muscle fibers. Treatment of mouse tibialis anterior muscles with cardiotoxin to induce muscle degeneration/regeneration led to a large (ϳ14-fold) increase in the levels of utrophin A with a modest change in expression of its transcript (40%). Isolation of the mouse utrophin A 5-untranslated region (UTR) revealed that it is relatively long with a predicted high degree of secondary structure. In control muscles, the 5-UTR of utrophin A caused an inhibition upon translation of a reporter protein. Strikingly, this inhibition was removed during regeneration, indicating that expression of utrophin A in regenerating muscles is translationally regulated via its 5-UTR. Using bicistronic reporter vectors, we observed that this translational effect involves an internal ribosome entry site in the utrophin A 5-UTR. Thus, internal ribosome entry site-mediated translation of utrophin A can, at least partially, account for the discordant expression of utrophin A protein and transcript in regenerating muscle. These findings provide a novel target for up-regulating levels of utrophin A in Duchenne muscular dystrophy muscle fibers via pharmacological interventions.

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Section: Discussioncontrasting

confidence: 60%

The Utrophin A 5′-Untranslated Region Confers Internal Ribosome Entry Site-mediated Translational Control during Regeneration of Skeletal Muscle Fibers

Miura

Thompson

Chakkalakal

et al. 2005

Journal of Biological Chemistry

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“…UTRN upregulation is implicated in the immune reaction in Duchenne muscular dystrophy mouse models (44). UTRN upregulation induced by proinflammatory factor-associated post-transcriptional mechanisms exhibits an antidystrophic effect (45). Therefore, the present study suggested that UPP1 and UTRN might act in the development and progression of PSS by affecting inflammation and immune reactions as well.…”

Section: Discussionmentioning

confidence: 55%

A six‑gene support vector machine classifier contributes to the diagnosis of pediatric septic shock

Long

Yang

2020

Mol Med Report

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Septic shock is induced by an uncontrolled inflammatory immune response to pathogens and the survival rate of patients with pediatric septic shock (PSS) is particularly low, with a mortality rate of 25-50%. The present study explored the mechanisms of PSS using four microarray datasets (GSe26378, GSe26440, GSe13904 and GSe4607) that were obtained from the Gene Expression Omnibus database. Based on the MetaDE package, the consistently differentially expressed genes (DEGs) in the four datasets were screened. Using the WGCNA package, the disease-associated modules and genes were identified. Subsequently, the optimal feature genes were further selected using the caret package. Finally, a support vector machine (SVM) classifier based on the optimal feature genes was built using the e1071 package. Initially, there were 2,699 consistent DEGs across the four datasets. From the 10 significantly stable modules across the datasets, four stable modules (including the magenta, purple, turquoise and yellow modules), in which the consistent DEGs were significantly enriched (P<0.05), were further screened. Subsequently, six optimal feature genes (including cysteine rich transmembrane module containing 1, S100 calcium binding protein A9, solute carrier family 2 member 14, stomatin, uridine phosphorylase 1 and utrophin) were selected from the genes in the four stable modules. Additionally, an effective SVM classifier was constructed based on the six optimal genes. The SVM classifier based on the six optimal genes has the potential to be applied for PSS diagnosis. This may improve the accuracy of early PSS diagnosis and suggest possible molecular targets for interventions.

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“…1a). Mononuclear infiltrates and myofiber edema were apparent in the left gastrocnemius, soleus and hamstring muscles, consistent with myositis induced by intramuscular adenovirus injection15, whereas muscles of uninjected limbs appeared normal (Fig. 1a).…”

mentioning

confidence: 65%

BMP type I receptor inhibition reduces heterotopic ossification

Deng

Lai

et al. 2008

Nat Med

562

610

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Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues 1-4 and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2)5. Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I Correspondence should be addressed to P.B.Y. (pbyu@partners.org). 8 Present address:

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Factors Associated with Induced Chronic Inflammation in mdx Skeletal Muscle Cause Posttranslational Stabilization and Augmentation of Extrasynaptic Sarcolemmal Utrophin

Cited by 16 publications

References 70 publications

The Utrophin A 5′-Untranslated Region Confers Internal Ribosome Entry Site-mediated Translational Control during Regeneration of Skeletal Muscle Fibers

The Utrophin A 5′-Untranslated Region Confers Internal Ribosome Entry Site-mediated Translational Control during Regeneration of Skeletal Muscle Fibers

A six‑gene support vector machine classifier contributes to the diagnosis of pediatric septic shock

BMP type I receptor inhibition reduces heterotopic ossification

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