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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

Age regulated gene expression trends change faster in OPMD(A) Expression trends in controls (grey) and expPABPN1 carriers (red). Similar expression trends were identified with k-means clustering using probe ID. (B) Examples of expression trends of 8 genes from clusters in A, in healthy controls (grey) or in exPABPN1 carriers at pre-symptomatic and symptomatic stages (red). Pre-symptomatic and symptomatic stages of OPMD are indicated.
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Figure 3: Age regulated gene expression trends change faster in OPMD(A) Expression trends in controls (grey) and expPABPN1 carriers (red). Similar expression trends were identified with k-means clustering using probe ID. (B) Examples of expression trends of 8 genes from clusters in A, in healthy controls (grey) or in exPABPN1 carriers at pre-symptomatic and symptomatic stages (red). Pre-symptomatic and symptomatic stages of OPMD are indicated.

Mentions: Close to 30 years separate the OPMD patients in our study from the elderly, but the remarkable overlap in expression profiles suggests that changes in OPMD initiate earlier or progress faster compared with normal aging. To identify expression trends k-means clustering was applied on the overlapping probes between OPMD and elderly. We compared trends per probe in a dataset derived from the healthy cohort age 17-89 years to those derived from expPABPN1 carriers age 31-74, and subsequently, unique genes were identified using Entrez ID. Two clusters of significant age-regulated genes showing accelerated (N=35) or decelerated (N=39) trends in OPMD were identified (Figure 3A, Supplementary Table 3). Examples of trends for selected genes are presented in Figure 3B. Among those are well-known regulators of aging such as the cell cycle regulators CDKN1A (p21) and OSBP, regulators of muscle cells and energy metabolism like LMOD1 and CHRNA1 or FAT1 and PRODH. These genes with accelerated expression changes in OPMD could contribute to disease progression and muscle weakness.


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)

Age regulated gene expression trends change faster in OPMD(A) Expression trends in controls (grey) and expPABPN1 carriers (red). Similar expression trends were identified with k-means clustering using probe ID. (B) Examples of expression trends of 8 genes from clusters in A, in healthy controls (grey) or in exPABPN1 carriers at pre-symptomatic and symptomatic stages (red). Pre-symptomatic and symptomatic stages of OPMD are indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Age regulated gene expression trends change faster in OPMD(A) Expression trends in controls (grey) and expPABPN1 carriers (red). Similar expression trends were identified with k-means clustering using probe ID. (B) Examples of expression trends of 8 genes from clusters in A, in healthy controls (grey) or in exPABPN1 carriers at pre-symptomatic and symptomatic stages (red). Pre-symptomatic and symptomatic stages of OPMD are indicated.
Mentions: Close to 30 years separate the OPMD patients in our study from the elderly, but the remarkable overlap in expression profiles suggests that changes in OPMD initiate earlier or progress faster compared with normal aging. To identify expression trends k-means clustering was applied on the overlapping probes between OPMD and elderly. We compared trends per probe in a dataset derived from the healthy cohort age 17-89 years to those derived from expPABPN1 carriers age 31-74, and subsequently, unique genes were identified using Entrez ID. Two clusters of significant age-regulated genes showing accelerated (N=35) or decelerated (N=39) trends in OPMD were identified (Figure 3A, Supplementary Table 3). Examples of trends for selected genes are presented in Figure 3B. Among those are well-known regulators of aging such as the cell cycle regulators CDKN1A (p21) and OSBP, regulators of muscle cells and energy metabolism like LMOD1 and CHRNA1 or FAT1 and PRODH. These genes with accelerated expression changes in OPMD could contribute to disease progression and muscle weakness.

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