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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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RT-qPCR analysis of PABPN1 expression trends in OPMD and during muscle aging(A) Box plot shows PABPN1expression in Vastus lateralis from expPABPN1 carriers at a pre-symptomatic (pre-symp) or symptomatic (OPMD) stages, and age-matching control groups. (B) Box plot showsPABPN1expression in blood form OPMD patients and controls. (C) Scatter plot shows PABPN1expression in 78 healthy controls age 17-89 years. Male and female samples are indicated in black and grey, respectively. A quadratic fit is shown with a black line (a), and linear fits are for the age groups: 17-42 years (b) or 43-89 years (c) are denoted in grey. The table summarizes p-values and Beta ± standard errors, which were calculated after gender correction. Fold-changes were calculated after normalization of GUSB housekeeping gene and to control group age 17-22 years (A, C) or age matching controls (B). N denotes the number of samples in each group.
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Figure 5: RT-qPCR analysis of PABPN1 expression trends in OPMD and during muscle aging(A) Box plot shows PABPN1expression in Vastus lateralis from expPABPN1 carriers at a pre-symptomatic (pre-symp) or symptomatic (OPMD) stages, and age-matching control groups. (B) Box plot showsPABPN1expression in blood form OPMD patients and controls. (C) Scatter plot shows PABPN1expression in 78 healthy controls age 17-89 years. Male and female samples are indicated in black and grey, respectively. A quadratic fit is shown with a black line (a), and linear fits are for the age groups: 17-42 years (b) or 43-89 years (c) are denoted in grey. The table summarizes p-values and Beta ± standard errors, which were calculated after gender correction. Fold-changes were calculated after normalization of GUSB housekeeping gene and to control group age 17-22 years (A, C) or age matching controls (B). N denotes the number of samples in each group.

Mentions: Since mutations in PABPN1 are the genetic cause for OPMD, we next validated the decline in PABPN1 mRNA levels using RT-qPCR using an extended cohort of skeletal muscle biopsies. A significant and pronounced decrease in expression was found in OPMD compared with age-matching controls, while at the pre-symptomatic stage PABPN1 levels did not significantly change (Figure 5A). This suggests that symptoms in OPMD patients are associated with a decrease in PABPN1 expression.


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)

RT-qPCR analysis of PABPN1 expression trends in OPMD and during muscle aging(A) Box plot shows PABPN1expression in Vastus lateralis from expPABPN1 carriers at a pre-symptomatic (pre-symp) or symptomatic (OPMD) stages, and age-matching control groups. (B) Box plot showsPABPN1expression in blood form OPMD patients and controls. (C) Scatter plot shows PABPN1expression in 78 healthy controls age 17-89 years. Male and female samples are indicated in black and grey, respectively. A quadratic fit is shown with a black line (a), and linear fits are for the age groups: 17-42 years (b) or 43-89 years (c) are denoted in grey. The table summarizes p-values and Beta ± standard errors, which were calculated after gender correction. Fold-changes were calculated after normalization of GUSB housekeeping gene and to control group age 17-22 years (A, C) or age matching controls (B). N denotes the number of samples in each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: RT-qPCR analysis of PABPN1 expression trends in OPMD and during muscle aging(A) Box plot shows PABPN1expression in Vastus lateralis from expPABPN1 carriers at a pre-symptomatic (pre-symp) or symptomatic (OPMD) stages, and age-matching control groups. (B) Box plot showsPABPN1expression in blood form OPMD patients and controls. (C) Scatter plot shows PABPN1expression in 78 healthy controls age 17-89 years. Male and female samples are indicated in black and grey, respectively. A quadratic fit is shown with a black line (a), and linear fits are for the age groups: 17-42 years (b) or 43-89 years (c) are denoted in grey. The table summarizes p-values and Beta ± standard errors, which were calculated after gender correction. Fold-changes were calculated after normalization of GUSB housekeeping gene and to control group age 17-22 years (A, C) or age matching controls (B). N denotes the number of samples in each group.
Mentions: Since mutations in PABPN1 are the genetic cause for OPMD, we next validated the decline in PABPN1 mRNA levels using RT-qPCR using an extended cohort of skeletal muscle biopsies. A significant and pronounced decrease in expression was found in OPMD compared with age-matching controls, while at the pre-symptomatic stage PABPN1 levels did not significantly change (Figure 5A). This suggests that symptoms in OPMD patients are associated with a decrease in PABPN1 expression.

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