The ribosomal DNA landscape of mammalian muscle during acute and chronic physiological stress

Abstract

Ribosomal DNA (rDNA) is a highly repetitive and complex locus within the mammalian genome that exhibits substantial inter-individual variation in number of rDNA copies and epigenetic regulation. Nonetheless, our understanding of rDNA biology in skeletal muscle during periods of physiological stress is limited. Using publicly available whole genome and reduced representative bisulfite sequencing data sets, we identify a concurrent reduction in both the number of rDNA copies and the methylation profile of the rDNA in aged vs young mice, supported by large effect sizes and permutation testing, with significant reductions in methylation of the 18S coding unit in aged, compared to young controls (p = 0.024). We found a strong positive correlation between rDNA copy number and 18S methylation across both young and aged mice (p = 0.004; Spearman rho = 0.842). After analysing publicly available muscle (skeletal and cardiac) data sets following acute insult (endurance exercise, cancer cachexia, spinal cord injury), we do not observe a similarly coordinated epi-genetic modification in rDNA biology but uncover tissue and sex-specific differences in rDNA copy number or methylation status, in isolation. These findings suggest ageing as a unique physiological insult in which coordinated epi-genomic remodelling of the rDNA region appears, representing a previously underappreciated feature of the muscle ageing trajectory.