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

• Published in: eLife Vol. 6
• Main Authors: Brinegar, Amy E, Xia, Zheng, Loehr, James Anthony, Li, Wei, Rodney, George Gerald, Cooper, Thomas A
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 11.08.2017; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Alternative Splicing; Animals; Animals, Newborn; Biochemistry; Calcineurin; Calcineurin - biosynthesis; Calcineurin - genetics; Calcium; Calcium - metabolism; Cell Biology; Cell culture; Cooper, Thomas A; Developmental Biology; Embryos; Fetuses; Gene expression; Gene Expression Profiling; Genes; Genomes; Isoforms; Localization; Medicine; Metabolism; Mice; Muscle contraction; Muscle, Skeletal - growth & development; Musculoskeletal system; Nfat; NFATC Transcription Factors - metabolism; Phosphatases; Physiological aspects; Physiology; postnatal development; Proteins; Ribonucleic acid; RNA; Rodents; Skeletal muscle; Transcription; stem cells; cell biology; alternative splicing; developmental biology; none; calcineurin; skeletal muscle; Nfat; postnatal development
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.27192

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 2 weeks after birth are particularly dynamic for differential gene expression and alternative splicing transitions, and calcium-handling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of the 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 target Nfatc3, and/or affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of alternative splicing during muscle postnatal development.