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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

The transcriptome of the OPMD mouse model is highly associated with aging(A) Volcano plot shows the distribution of significantly deregulated genes (P = 0.05; indicated with a dashed line) in 6 week-old A17.1 mice against fold-change. Smaller P-value and higher fold-change suggests a higher impact in OPMD. For every gene a literature-associated weight with the ‘Aging' concept is assigned, and a normalized association-weight is presented with a circle on a linear scale between 0.05 and 1, where 1 equals the highest association. (B) Hierarchical clustering arrangements of 104 datasets in a literature-aided meta-analysis. Shades of blue indicate degree of similarities: from weak (white) to strong (dark blue). Three skeletal muscle aging-related datasets cluster together with the OPMD dataset of 6 week-old mice (highlighted in red). The clusters associated with muscular dystrophies and other myopathies are highlighted in green and blue, respectively.
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Figure 2: The transcriptome of the OPMD mouse model is highly associated with aging(A) Volcano plot shows the distribution of significantly deregulated genes (P = 0.05; indicated with a dashed line) in 6 week-old A17.1 mice against fold-change. Smaller P-value and higher fold-change suggests a higher impact in OPMD. For every gene a literature-associated weight with the ‘Aging' concept is assigned, and a normalized association-weight is presented with a circle on a linear scale between 0.05 and 1, where 1 equals the highest association. (B) Hierarchical clustering arrangements of 104 datasets in a literature-aided meta-analysis. Shades of blue indicate degree of similarities: from weak (white) to strong (dark blue). Three skeletal muscle aging-related datasets cluster together with the OPMD dataset of 6 week-old mice (highlighted in red). The clusters associated with muscular dystrophies and other myopathies are highlighted in green and blue, respectively.

Mentions: We further studied the association of the OPMD transcriptome with aging using the transcriptome of the A17.1 mouse at 6-weeks old, as muscle weakness is not obvious at that age (Trollet et al., 2010). In the A17.1 mouse expPABPN1 is overexpressed under a muscle-specific promoter resulting in severe muscle weakness (Davies et al., 2005) and muscle atrophy at an early age [15]. A literature-aided association study of the differentially expressed genes in the A17.1 muscles of 6 weeks-old mice showed that a large subset of these genes strongly associates with the aging concept (Figure 2A). The fold-change for the genes with a high association-weight score was large (Figure 2A), indicating that well-known aging genes are highly dysregulated in this mouse model.


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)

The transcriptome of the OPMD mouse model is highly associated with aging(A) Volcano plot shows the distribution of significantly deregulated genes (P = 0.05; indicated with a dashed line) in 6 week-old A17.1 mice against fold-change. Smaller P-value and higher fold-change suggests a higher impact in OPMD. For every gene a literature-associated weight with the ‘Aging' concept is assigned, and a normalized association-weight is presented with a circle on a linear scale between 0.05 and 1, where 1 equals the highest association. (B) Hierarchical clustering arrangements of 104 datasets in a literature-aided meta-analysis. Shades of blue indicate degree of similarities: from weak (white) to strong (dark blue). Three skeletal muscle aging-related datasets cluster together with the OPMD dataset of 6 week-old mice (highlighted in red). The clusters associated with muscular dystrophies and other myopathies are highlighted in green and blue, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: The transcriptome of the OPMD mouse model is highly associated with aging(A) Volcano plot shows the distribution of significantly deregulated genes (P = 0.05; indicated with a dashed line) in 6 week-old A17.1 mice against fold-change. Smaller P-value and higher fold-change suggests a higher impact in OPMD. For every gene a literature-associated weight with the ‘Aging' concept is assigned, and a normalized association-weight is presented with a circle on a linear scale between 0.05 and 1, where 1 equals the highest association. (B) Hierarchical clustering arrangements of 104 datasets in a literature-aided meta-analysis. Shades of blue indicate degree of similarities: from weak (white) to strong (dark blue). Three skeletal muscle aging-related datasets cluster together with the OPMD dataset of 6 week-old mice (highlighted in red). The clusters associated with muscular dystrophies and other myopathies are highlighted in green and blue, respectively.
Mentions: We further studied the association of the OPMD transcriptome with aging using the transcriptome of the A17.1 mouse at 6-weeks old, as muscle weakness is not obvious at that age (Trollet et al., 2010). In the A17.1 mouse expPABPN1 is overexpressed under a muscle-specific promoter resulting in severe muscle weakness (Davies et al., 2005) and muscle atrophy at an early age [15]. A literature-aided association study of the differentially expressed genes in the A17.1 muscles of 6 weeks-old mice showed that a large subset of these genes strongly associates with the aging concept (Figure 2A). The fold-change for the genes with a high association-weight score was large (Figure 2A), indicating that well-known aging genes are highly dysregulated in this mouse model.

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