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A decline in PABPN1 induces progressive muscle weakness in oculopharyngeal muscle dystrophy and in muscle aging.

Anvar SY, Raz Y, Verway N, van der Sluijs B, Venema A, Goeman JJ, Vissing J, van der Maarel SM, 't Hoen PA, van Engelen BG, Raz V - Aging (Albany NY) (2013)

Bottom Line: Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P<0.05).Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels.We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

View Article: PubMed Central - PubMed

Affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, the Netherlands.

ABSTRACT
Oculopharyngeal muscular dystrophy (OPMD) is caused by trinucleotide repeat expansion mutations in Poly(A) binding protein 1 (PABPN1). PABPN1 is a regulator of mRNA stability and is ubiquitously expressed. Here we investigated how symptoms in OPMD initiate only at midlife and why a subset of skeletal muscles is predominantly affected. Genome-wide RNA expression profiles from Vastus lateralis muscles human carriers of expanded-PABPN1 at pre-symptomatic and symptomatic stages were compared with healthy controls. Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P<0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, but trends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis muscles from the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated in OPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

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Related in: MedlinePlus

Deregulation of the Spliceosome in both OPMD and elderly(A) Bar-chart shows fold-change of spliceosome genes in OPMD and elderly from the transcriptome studies. P-values are indicated: * P<0.05, ** P<0.005, *** P<0.0005. In bold are gene-hubs in the OPMD-affected spliceosome network (B). A schematic gene network presentation of OPMD-regulated genes that are grouped in the spliceosome GO category. PABPN1 is highlighted
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Figure 4: Deregulation of the Spliceosome in both OPMD and elderly(A) Bar-chart shows fold-change of spliceosome genes in OPMD and elderly from the transcriptome studies. P-values are indicated: * P<0.05, ** P<0.005, *** P<0.0005. In bold are gene-hubs in the OPMD-affected spliceosome network (B). A schematic gene network presentation of OPMD-regulated genes that are grouped in the spliceosome GO category. PABPN1 is highlighted

Mentions: The mRNA processing and spliceosome GO-terms were the most significantly affected in both OPMD and elderly datasets (Table 2). Noticeably, the majority of the dysregulated genes in this category were down regulated (Figure 4A). Network analysis suggests that central hubs are affected in both OPMD and elderly, including PABPN1 (Figure 4B).


A decline in PABPN1 induces progressive muscle weakness in oculopharyngeal muscle dystrophy and in muscle aging.

Anvar SY, Raz Y, Verway N, van der Sluijs B, Venema A, Goeman JJ, Vissing J, van der Maarel SM, 't Hoen PA, van Engelen BG, Raz V - Aging (Albany NY) (2013)

Deregulation of the Spliceosome in both OPMD and elderly(A) Bar-chart shows fold-change of spliceosome genes in OPMD and elderly from the transcriptome studies. P-values are indicated: * P<0.05, ** P<0.005, *** P<0.0005. In bold are gene-hubs in the OPMD-affected spliceosome network (B). A schematic gene network presentation of OPMD-regulated genes that are grouped in the spliceosome GO category. PABPN1 is highlighted
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824410&req=5

Figure 4: Deregulation of the Spliceosome in both OPMD and elderly(A) Bar-chart shows fold-change of spliceosome genes in OPMD and elderly from the transcriptome studies. P-values are indicated: * P<0.05, ** P<0.005, *** P<0.0005. In bold are gene-hubs in the OPMD-affected spliceosome network (B). A schematic gene network presentation of OPMD-regulated genes that are grouped in the spliceosome GO category. PABPN1 is highlighted
Mentions: The mRNA processing and spliceosome GO-terms were the most significantly affected in both OPMD and elderly datasets (Table 2). Noticeably, the majority of the dysregulated genes in this category were down regulated (Figure 4A). Network analysis suggests that central hubs are affected in both OPMD and elderly, including PABPN1 (Figure 4B).

Bottom Line: Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P<0.05).Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels.We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

View Article: PubMed Central - PubMed

Affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, the Netherlands.

ABSTRACT
Oculopharyngeal muscular dystrophy (OPMD) is caused by trinucleotide repeat expansion mutations in Poly(A) binding protein 1 (PABPN1). PABPN1 is a regulator of mRNA stability and is ubiquitously expressed. Here we investigated how symptoms in OPMD initiate only at midlife and why a subset of skeletal muscles is predominantly affected. Genome-wide RNA expression profiles from Vastus lateralis muscles human carriers of expanded-PABPN1 at pre-symptomatic and symptomatic stages were compared with healthy controls. Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P<0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, but trends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis muscles from the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated in OPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

Show MeSH
Related in: MedlinePlus