Abstract
Pre-mRNA splicing plays an important role in muscle function and diseases. The RNA binding motif 20 (RBM20) is a splicing factor that is predominantly expressed in muscle tissues and primarily regulates pre-mRNA splicing of Ttn, encoding a giant muscle protein titin that is responsible for muscle function and diseases. RBM20-mediated Ttn splicing has been mostly studied in heart muscle, but not in skeletal muscle. In this study, we investigated splicing specificity in different muscle types in Rbm20 knockout rats and hormonal effects on RBM20-mediated splicing both in cellulo and in vivo studies. The results revealed that RBM20 is differentially expressed across muscles and RBM20-mediated splicing is muscle-type specific. In the presence of RBM20, Ttn splicing responds to hormones in a muscle-type dependent manner, while in the absence of RBM20, Ttn splicing is not affected by hormones. In differentiated and undifferentiated C2C12 cells, RBM20-mediated splicing in response to hormonal effects is mainly through genomic signaling pathway. The knowledge gained from this study may help further understand muscle-specific gene splicing in response to hormone stimuli in different muscle types.
Highlights
Skeletal muscle comprises around 40% of the body weight in vertebrate animals, including humans, and supports multiple bodily functions such as body movement through muscle contraction [1]
RNA binding motif 20 (RBM20)-mediated Ttn splicing through hormone stimuli has been studied in heart muscle [34,35], but little is known about it in skeletal muscles
We examined Ttn splicing pattern and RBM20 expression levels in different muscles and determined how hormones modulate Ttn splicing through RBM20 expression in skeletal muscles
Summary
Skeletal muscle comprises around 40% of the body weight in vertebrate animals, including humans, and supports multiple bodily functions such as body movement through muscle contraction [1]. Titin has numerous isoforms resulting from alternative splicing among 363 exons [4,5,6,7] These isoforms are mainly generated by the extensive alternative splicing in the middle of the immunoglobulin (Ig) region and the PEVK (proline [P], glutamate [E], valine [V], and lysine [K]) domain [8,9,10,11,12]. The Ig region and the PEVK domain are the major components of the titin spring element that generates passive forces when skeletal muscle contracts [13,14,15]. Alternative titin exon usages and titin size switching resulting from alternative splicing may interrupt mechanosensing signals for muscle function and hypertrophy
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