Abstract
Random errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.
Highlights
Random errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades
While germline transmission of Rps2 alleles: wild type (Rps2WT) and Rps2loxP alleles was observed in 57% and 30% of the progeny, respectively, fully excised mice bearing only the Rps2A226Y allele have never been detected in the 168 pups analyzed (Supplementary Fig. 2b)
The limitations of genetic mosaicism in the A226Y model notwithstanding, our findings point to a prominent age-dependent response to error-prone protein synthesis in skeletal muscle
Summary
Random errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. We studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. The idea that aging and age-related diseases may be related to a decrease in protein synthesis accuracy dates back to the early 1960s, culminating in the error catastrophe theory of aging[2,3]. The capacity of the proteostasis network is thought to decline during aging, contributing to the development of age-related diseases[14,15] In muscle, this takes the form of sarcopenia, the age-associated decline in skeletal muscle function and mass[16,17]. Rams increase the physiological error rate of translation in a stochastic manner by affecting the initial phase of tRNA selection resulting in reduced discrimination against near-cognate tRNAs and in randomly dispersed amino acid misincorporations into the primary sequence of a protein[24,25]
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