Transcriptomic characterization of postnatal muscle maturation in mice, with a focus on myopathy-associated genes.

Abstract

Gene differential expression (DE) and alternative splicing (AS) are mechanisms that give rise to a plethora of tissue-specific transcripts. While these mechanisms have been studied in various tissues, their role during muscle maturation is not well understood. Since this stage of development is impaired in multiple muscular diseases, we used RNA-seq to analyze transcriptome remodeling in skeletal muscle from late embryonic stage (E18.5) to adult mouse (7 weeks). Major transcriptomic changes were detected, especially in the first two weeks after birth with a total of 8571 DE genes and 3096 AS genes. Comparison of these two mechanisms showed that they regulate different biological processes essential for the structure and function of skeletal muscle. Investigation of genes mutated in muscle disorders revealed previously unknown transcripts. In particular, we validated a novel exon in Lrp4, a gene mutated in congenital myasthenia, in mice and human. Overall, the characterization of the transcriptome in disease-relevant tissues revealed key pathways in the regulation of tissue maturation and function. Importantly, the exhaustive description of AS and resulting transcripts can improve genetic diagnosis.