Heritability assessment of cartilage metabolism. A twin study on circulating procollagen IIA N-terminal propeptide (PIIANP)

SummaryObjectiveThe aim of this investigation was to estimate the heritability of circulating collagen IIA N-terminal propeptide (PIIANP) by studying mono- and dizygotic healthy twin pairs at different age and both genders.Design598 monozygotic (MZ) and dizygotic (DZ) twin individuals aged 18–59 years were recruited from the Danish Twin Registry. PIIANP was measured by competitive ELISA. The similarity of circulating PIIANP among MZ and DZ twins was assessed by intraclass correlations according to traits. The heritability was estimated by variance component analysis accounting for additive and dominant genetic factors as well as shared and non-shared environment but ignoring epistasis (genetic inter-locus interaction) and gene–environment interaction.ResultsThe intraclass correlation of PIIANP in MZ and DZ twins was 0.69 (0.60–0.76) and 0.46 (0.34–0.58) respectively indicating a significant genetic impact on PIIANP in serum. Additive genetic effects explained 45% (21–70%), shared environment 24% (7–53%) and non-shared environment 31% (24–39%) of the total variance. The heritability estimate did not differ across ages and between genders.ConclusionsThe study shows that approximately 45% of the collagen IIA synthesis as assessed by the collagen IIA N-terminal propeptide in serum is attributable to genetic effectors while individual and shared environment account for 24% and 31% respectively. The heritability does not differ between genders or according to age

Alternative polyadenylation utilization results in ribosome assembly and mRNA translation deficiencies in a model for muscle aging

Aging-associated muscle wasting is regulated by multiple molecular processes, whereby aberrant mRNA processing regulation induces muscle wasting. The poly(A)-binding protein nuclear 1 (PABPN1) regulates polyadenylation site (PAS) utilization, in the absence of PABPN1 the alternative polyadenylation (APA) is utilized. Reduced PABPN1 levels induce muscle wasting where the expression of cellular processes regulating protein homeostasis, the ubiquitin-proteasome system, and translation, are robustly dysregulated. Translation is affected by mRNA levels, but PABPN1 impact on translation is not fully understood. Here we show that a persistent reduction in PABPN1 levels led to a significant loss of translation efficiency. RNA-sequencing of rRNA-depleted libraries from polysome traces revealed reduced mRNA abundance across ribosomal fractions, as well as reduced levels of small RNAs. We show that the abundance of translated mRNAs in the polysomes correlated with PAS switches at the 3 '-UTR. Those mRNAs are enriched in cellular processes that are essential for proper muscle function. This study suggests that the effect of PABPN1 on translation efficiency impacts protein homeostasis in aging-associated muscle atrophy