Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions

Postnatal development of skeletal muscle is a highly dynamic period of tissue remodeling. Here we used RNA-seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrate that alternative splicing developmental transitions impact muscle physiology. The first two weeks after birth are particularly dynamic for differential gene expression and AS transitions, and calcium-handling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of three calcineurin A genes, calcium-dependent phosphatases that regulate multiple aspects of muscle biology. Redirected splicing of calcineurin A to the fetal isoforms in adult muscle and in differentiated C2C12 slows the timing of muscle relaxation, promotes nuclear localization of calcineurin targets Nfatc3 and Nfatc2, and affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of AS during muscle postnatal development.