Removal of immunoglobulin-like domains from titin's spring segment alters titin splicing in mouse skeletal muscle and causes myopathy.

Titin is a molecular spring that determines the passive stiffness of muscle cells. Changes in tidn's stiffness occur in various myopathies, but whether these are a cause or an effect of the disease is unknown. We studied a novel mouse model in which titin's stiffness was slightly increased by deleting nine immunoglobulin (Ig)-like domains from ti-tin's constitutively expressed proximal tandem Ig segment (IG KO). KO mice displayed mild kyphosis, a phenotype commonly associated with skeletal muscle myopathy. Slow muscles were atrophic with alterations in myosin iso-form expression; functional studies in soleus muscle revealed a reduced specific twitch force. Exon expression analysis showed that KO mice underwent additional changes in titin splicing to yield smaller than expected titin isoforms that were much stiffer than expected. Additionally, splicing occurred in the PEVK region of titin, a find-ing confirmed at the protein level. The titin-binding protein Ankrdl was highly increased in the IG KO, but this did not play a role in generating small titin isoforms because titin expression was unaltered in IG KO mice crossed with Ankrdl-deficient mice. In contrast, the splicing factor RBM20 (RNA-binding motif 20) was also significantly in-creased in IGKOmice, and additional differential splicing was reversed in IG KOmice crossed with a mouse with reduced RBM20 activity. Thus, increasing titin's stiffness triggers pathological changes in skeletal muscle, with an important role played by RBM20. [ABSTRACT FROM AUTHOR]