Muscle wasting in chronic kidney disease.

Loss of lean body mass is a relevant component of the cachexia, or protein energy wasting (PEW), syndrome. Reduced muscle mass seems to be the most solid criterion for the presence of cachexia/PEW in patients with chronic kidney disease (CKD), and those with greater muscle mass loss have a higher risk of death. Children with CKD have many risk factors for lean mass and muscle wasting, including poor appetite, inflammation, growth hormone resistance, and metabolic acidosis. Mortality risks in patients with CKD increases as body mass index (BMI) and weight decreases. However, data regarding cachexia/PEW and muscle wasting in children with CKD is scarce due to lack of consensus in diagnostic criteria and an appropriate investigative methodology. Further research is urgently needed to address this important complication in the pediatric CKD setting, which may have fundamental impact on clinical outcomes.

Identification of elements in human long 3' UTRs that inhibit nonsense-mediated decay.

The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3' UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3' UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3' UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3' UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMD-inhibiting cis elements in the first 200 nt. A smaller subset of long 3' UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3' UTRs.