Bortezomib Partially Improves Laminin α2 Chain–Deficient Muscular Dystrophy

Körner, Zandra; Fontes-Oliveira, Cibely C.; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

doi:10.1016/j.ajpath.2014.01.019

Cited by 29 publications

(43 citation statements)

References 64 publications

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“…However, bortezomib did not affect miR-206 plasma levels. This is consistent with observations that bortezomib does not significantly reduce myofiber regeneration in dy 3K /dy 3K mice (Körner et al, 2014). In summary, the partial normalization of miR-1 and miR-133a in response to bortezomib administration indicates that these miRNAs are promising disease biomarkers for MDC1A.…”

Section: Resultssupporting

confidence: 93%

“…Increased proteasomal activity is a feature of MDC1A and recent studies demonstrated that proteasome inhibition partially improves muscle integrity in dy 3K /dy 3K mice accompanied by increased expression of miR-1 and miR-133a (Carmignac et al, 2011; Körner et al, 2014). To determine if reduced muscle pathology had an impact on plasma levels of dysregulated miRNAs, dy 3K /dy 3K mice were given bortezomib (a proteasome inhibitor).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we have taken advantage of a proteasome inhibitor that reduces the dy 3K /dy 3K pathology (Körner et al, 2014), to investigate whether reduction in muscle pathology correlates with levels of muscle-specific miRNAs in plasma.…”

Section: Introductionmentioning

confidence: 99%

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Laminin Î±2 Chain-Deficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma

Holmberg

Alajbegovic

Gawlik

et al. 2014

Front. Aging Neurosci.

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microRNAs (miRNAs) are widespread regulators of gene expression, but little is known of their potential roles in congenital muscular dystrophy type 1A (MDC1A). MDC1A is a severe form of muscular dystrophy caused by mutations in the gene encoding laminin α2 chain. To gain insight into the pathophysiological roles of miRNAs associated with MDC1A pathology, laminin α2 chain-deficient mice were evaluated by quantitative PCR. We demonstrate that expression of muscle-specific miR-1, miR-133a, and miR-206 is deregulated in laminin α2 chain-deficient muscle. Furthermore, expression of miR-223 and miR-21, associated with immune cell infiltration and fibrosis, respectively, is altered. Finally, we show that plasma levels of muscle-specific miRNAs are markedly elevated in laminin α2 chain-deficient mice and partially normalized in response to proteasome inhibition therapy. Altogether, our data suggest important roles for miRNAs in MDC1A pathology and we propose plasma levels of muscle-specific miRNAs as promising biomarkers for the progression of MDC1A.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Laminin Î±2 Chain-Deficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma

Holmberg

Alajbegovic

Gawlik

et al. 2014

Front. Aging Neurosci.

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“…[26][27][28][29][30][31][32][33] However, degradation of proteins by the ubiquitinproteasome is a complex ATP-dependent multistage process Abbreviations: Del, deletion; Hypercontr., hypercontracted fibers.…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy

Assereto

Piccirillo

Baratto

et al. 2016

Laboratory Investigation

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Activation of the proteasome pathway is one of the secondary processes of cell damage, which ultimately lead to muscle degeneration and necrosis in Duchenne muscular dystrophy (DMD). In mdx mice, the proteasome inhibitor bortezomib up-regulates the membrane expression of members of the dystrophin complex and reduces the inflammatory reaction. However, chronic inhibition of the 26S proteasome may be toxic, as indicated by the systemic side-effects caused by this drug. Therefore, we sought to determine the components of the ubiquitin-proteasome pathway that are specifically activated in human dystrophin-deficient muscles. The analysis of a cohort of patients with genetically determined DMD or Becker muscular dystrophy (BMD) unveiled a selective up-regulation of the ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). The induction of TRIM32 was due to a transcriptional effect and it correlated with disease severity in BMD patients. In contrast, atrogin1 and muscle RING-finger protein-1 (MuRF-1), which are strongly increased in distinct types of muscular atrophy, were not affected by the DMD dystrophic process. Knock-out models showed that TRIM32 is involved in ubiquitination of muscle cytoskeletal proteins as well as of protein inhibitor of activated STAT protein gamma (Piasγ) and N-myc downstream-regulated gene, two inhibitors of satellite cell proliferation and differentiation. Accordingly, we showed that in DMD/BMD muscle tissue, TRIM32 induction was more pronounced in regenerating myofibers rather than in necrotic muscle cells, thus pointing out a role of this protein in the regulation of human myoblast cell fate. This finding highlights TRIM32 as a possible therapeutic target to favor skeletal muscle regeneration in DMD patients.

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“…Interestingly, proteasome inhibitors have been used in dy(3K)/dy(3K) mice to partially alleviate detrimental phenotypes for muscle wasting diseases such as congenital muscular dystrophy, thus improving body weight, locomotion, and survival (Korner et al, 2014). Specifically, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A muscle tissue (Korner et al, 2014).…”

Section: The Role Of the 20s Proteasome In Aging And In Aging-relmentioning

confidence: 99%

Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways

Raynes

Pomatto

Davies

2016

Molecular Aspects of Medicine

188

155

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The proteasome is a ubiquitous and highly plastic multi-subunit protease with multi-catalytic activity that is conserved in all eukaryotes. The most widely known function of the proteasome is protein degradation through the 26S ubiquitin-proteasome system, responsible for the vast majority of protein degradation during homeostasis. However, the proteasome also plays an important role in adaptive immune responses and adaptation to oxidative stress. The unbound 20S proteasome, the core common to all proteasome conformations, is the main protease responsible for degrading oxidized proteins. During periods of acute stress, the 19S regulatory cap of the 26S proteasome disassociates from the proteolytic core, allowing for immediate ATP/ubiquitin-independent protein degradation by the 20S proteasome. Despite the abundance of unbound 20S proteasome compared to other proteasomal conformations, many publications fail to distinguish between the two proteolytic systems and often regard the 26S proteasome as the dominant protease. Further confounding the issue are the differential roles these two proteolytic systems have in adaptation and aging. In this review, we will summarize the increasing evidence that the 20S core proteasome constitutes the major conformation of the proteasome system and that it is far from a latent protease requiring activation by binding regulators.

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Bortezomib Partially Improves Laminin α2 Chain–Deficient Muscular Dystrophy

Cited by 29 publications

References 64 publications

Laminin Î±2 Chain-Deficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma

Laminin Î±2 Chain-Deficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma

The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy

Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways

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