Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity

Titins are megadalton-sized filamentous polypeptides of vertebrate striated muscle. The I-band region of titin underlies the myofibrillar passive tens ion response to stretch. Here, we show how titins with highly diverse I-ban d structures and elastic properties are expressed from a single gene. The d ifferentially expressed tandem-Ig, PEVK, and N2B spring elements of titin a re coded by 158 exons, which are contained within a 106-kb genomic segment and are all subject to tissue-specific skipping events. In ventricular hear t muscle, exons 101 kb apart are joined, leading to the exclusion of 155 ex ons and the expression of a 2.97-MDa cardiac titin N2B isoform. The atria o f mammalian hearts also express larger titins by the exclusion of 90 to 100 exons (cardiac N2BA titin with 3.3 MDa). In the soleus and psoas skeletal muscles, different exon-skipping pathways produce titin transcripts that co de for 3.7- and 3.35-MDa titin isoforms, respectively. Mechanical and struc tural studies indicate that the exon-skipping pathways modulate the fractio nal extensions of the tandem Ig and PEVK segments, thereby influencing myof ibrillar elasticity. Within the mammalian heart, expression of different le vels of N2B and N2BA titins likely contributes to the elastic diversity of atrial and ventricular myofibrils.