Limits...
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.

Show MeSH

Related in: MedlinePlus

Similar expression profiles in OPMD and elderly muscles(A) Venn diagram shows the number of affected genes (p ≤0.01) in OPMD, elderly overlapping genes. The percentage of similar gene direction and the direction (up or down) are listed. For each group the mean age ± standard deviation are denoted. (B) Cumulative distribution function (CDF) plots show the distribution of normalized literature association-weights of commonly deregulated genes between OPMD and elderly with the concepts: Aging, Muscle contraction, Oxidative phospho-rylation, insulin signalling, TGFβsignalling, and the ubiquitin-proteasome system (UPS). Arrowheads indicate the maximum association weights. The further the curve shifts to the right, the higher the associations of the affected genes with the indicated concepts are. (C) Bar-chart shows fold-change of selected known age-regulated genes in elderly and in OPMD. P-values are indicated: * P≤0.01, ** P<0.005, *** P<0.0005.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824410&req=5

Figure 1: Similar expression profiles in OPMD and elderly muscles(A) Venn diagram shows the number of affected genes (p ≤0.01) in OPMD, elderly overlapping genes. The percentage of similar gene direction and the direction (up or down) are listed. For each group the mean age ± standard deviation are denoted. (B) Cumulative distribution function (CDF) plots show the distribution of normalized literature association-weights of commonly deregulated genes between OPMD and elderly with the concepts: Aging, Muscle contraction, Oxidative phospho-rylation, insulin signalling, TGFβsignalling, and the ubiquitin-proteasome system (UPS). Arrowheads indicate the maximum association weights. The further the curve shifts to the right, the higher the associations of the affected genes with the indicated concepts are. (C) Bar-chart shows fold-change of selected known age-regulated genes in elderly and in OPMD. P-values are indicated: * P≤0.01, ** P<0.005, *** P<0.0005.

Mentions: If molecular changes in OPMD are similar to these in muscle aging similarity in dysregulated genes and expression trends is expected. We compared OPMD expression profiles (mean age 56 ± 5) with those of elderly (>85 years) (Supplementary Table 1). It is relevant to note that OPMD patients were under 70 years-old and therefore may not considered as elderly. VL muscles from healthy controls were sampled same as the OPMD biopsies and expression profiles were generated on the same platform. Expression profiles in OPMD and elderly were generated with the same control group (mean age 56 ± 5). Close to one third of the genes affected in elderly overlapped with those affected in OPMD (Figure 1A), and the same directionality in fold-change was found for 84% of these genes. The majority of the overlapping genes (77%) were down regulated (Figure 1A). This observation is consistent with other studies that found a prominent transcriptional down-regulation in neurons from the elderly [23]. Gene Ontology (GO) analysis of OPMD- or elderly- regulated genes also revealed high similarities between significantly affected cellular and molecular functions (Table 2).


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)

Similar expression profiles in OPMD and elderly muscles(A) Venn diagram shows the number of affected genes (p ≤0.01) in OPMD, elderly overlapping genes. The percentage of similar gene direction and the direction (up or down) are listed. For each group the mean age ± standard deviation are denoted. (B) Cumulative distribution function (CDF) plots show the distribution of normalized literature association-weights of commonly deregulated genes between OPMD and elderly with the concepts: Aging, Muscle contraction, Oxidative phospho-rylation, insulin signalling, TGFβsignalling, and the ubiquitin-proteasome system (UPS). Arrowheads indicate the maximum association weights. The further the curve shifts to the right, the higher the associations of the affected genes with the indicated concepts are. (C) Bar-chart shows fold-change of selected known age-regulated genes in elderly and in OPMD. P-values are indicated: * P≤0.01, ** P<0.005, *** P<0.0005.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Similar expression profiles in OPMD and elderly muscles(A) Venn diagram shows the number of affected genes (p ≤0.01) in OPMD, elderly overlapping genes. The percentage of similar gene direction and the direction (up or down) are listed. For each group the mean age ± standard deviation are denoted. (B) Cumulative distribution function (CDF) plots show the distribution of normalized literature association-weights of commonly deregulated genes between OPMD and elderly with the concepts: Aging, Muscle contraction, Oxidative phospho-rylation, insulin signalling, TGFβsignalling, and the ubiquitin-proteasome system (UPS). Arrowheads indicate the maximum association weights. The further the curve shifts to the right, the higher the associations of the affected genes with the indicated concepts are. (C) Bar-chart shows fold-change of selected known age-regulated genes in elderly and in OPMD. P-values are indicated: * P≤0.01, ** P<0.005, *** P<0.0005.
Mentions: If molecular changes in OPMD are similar to these in muscle aging similarity in dysregulated genes and expression trends is expected. We compared OPMD expression profiles (mean age 56 ± 5) with those of elderly (>85 years) (Supplementary Table 1). It is relevant to note that OPMD patients were under 70 years-old and therefore may not considered as elderly. VL muscles from healthy controls were sampled same as the OPMD biopsies and expression profiles were generated on the same platform. Expression profiles in OPMD and elderly were generated with the same control group (mean age 56 ± 5). Close to one third of the genes affected in elderly overlapped with those affected in OPMD (Figure 1A), and the same directionality in fold-change was found for 84% of these genes. The majority of the overlapping genes (77%) were down regulated (Figure 1A). This observation is consistent with other studies that found a prominent transcriptional down-regulation in neurons from the elderly [23]. Gene Ontology (GO) analysis of OPMD- or elderly- regulated genes also revealed high similarities between significantly affected cellular and molecular functions (Table 2).

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