Ribosomal mistranslation activates an age-dependent program of dystrophic muscle wasting

Random errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. We investigated the impact of translation errors by studying whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of translation, if at all viable, presented any specific, possibly aging-related phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic, with tissue-dependent expression of Rps2-A226Y in 5-30% of cells. We observed a muscle-related phenotype with reduced grip strength and body weight. Analysis of gene expression in skeletal muscle using RNA-Seq revealed changes characteristic of muscle dystrophy occurring in an age-dependent manner, involving an interplay of PGC1a, FOXO3, mTOR, and glucocorticoids as key signalling pathways for muscle function and mitochondrial biogenesis. Our results highlight the relevance of translation accuracy, and show how disturbances thereof can contribute to age-related pathologies. Overall design: mRNA expression profiles of skeletal muscle from Rps2-A226Y mutant mice, expressed under a cre-lox system, and wild type (WT) ubiquitous Cre recombinase expressing mice, at 9 and 15 months of age.