Fig. 9

Schematic representation of physiological significant DAS of skeletal muscle genes via upstream splicing of RBPs. RBP splicing, downstream target splicing, and potential functional impact are highlighted here. Splicing patterns in ground and spaceflight are differentiated by blue and tan/orange boxes, respectively. Dotted lines represent directionality of proposed processes with corresponding text annotations. Solid lines represent RBP binding and splicing regulation with inhibition of such depicted by a red “X”. DAS of exon 2 of Mbnl1 determines the translational start site (TSS) of Mbnl1 mRNA and generates two distinct Mbnl1 RBP isoforms (ground, functionally intact; spaceflight, functionally impaired). While the functionally intact Mbnl1 isoform in ground binds freely to motif mapped regions of Ttn (PEVK domain-encoding exons) and Tnnt1 (exon 5), the functionally impaired Mbnl1 in spaceflight exhibits less activity and target RNA motif specificity, directing splicing away from the canonical splicing pathway (Ttn, concomitant exclusion of PEVK domain-encoding exons; Tnnt1, exon 5 exclusion) and towards an aberrant splicing pathway (Ttn, concomitant inclusion of PEVK domain-encoding exons; Tnnt1, exon 5 inclusion) that has been associated with the physiological adaptations of skeletal muscle to spaceflight, such as expanded fast-twitch fiber function and muscle atrophy