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

TY - JOUR

T1 - A decline in PABPN1 induces progressive muscle weakness in oculopharyngeal muscle dystrophy and in muscle aging

AU - Anvar, Seyed Yahya

AU - Raz, Yotam

AU - Verway, Nisha

AU - van der Sluijs, Barbara

AU - Venema, Andrea

AU - Goeman, Jelle J

AU - Vissing, John

AU - van der Maarel, Silvère M

AU - 't Hoen, Peter A C

AU - van Engelen, Baziel G M

AU - Raz, Vered

PY - 2013/6

Y1 - 2013/6

N2 - 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 investigatedhow 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 andsymptomatic 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 weresignificantly similar (P<0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, buttrends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis musclesfrom the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated inOPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defectsand morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 level sregulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

AB - 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 investigatedhow 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 andsymptomatic 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 weresignificantly similar (P<0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, buttrends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis musclesfrom the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated inOPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defectsand morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 level sregulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

M3 - Journal article

SN - 1945-4589

VL - 5

SP - 412

EP - 426

JO - Aging

JF - Aging

IS - 6

ER -