Question: 

The portion of the sarcomere not directly participating in actin-myosin interaction, the Z-disc/I-band, nevertheless has important structural and signaling functions. We ask how the Z-disc/I-band region participates in mechanotransduction/mechanosignaling events in health and disease. Of particular interest is the role of the giant protein titin, the backbone of the sarcomere.

Results: 

The I-band titin segment harbors a complex molecular spring whose main function is as a determinant of myocyte passive stiffness and whose mechanical properties can be variably tuned. Evidence suggests that the isoform-expression ratio of the cardiac titin springs determines the level of titin-based stiffness and that the isoform-pattern is deranged in heart failure. Interactions of titin with diverse molecules provide links to pathways regulating protein quality-control mechanisms and hypertrophic gene activation. Recent work has established a signaling hotspot in I-band titin, the cardiac-specific N2B-domain. Phosphorylation of a unique sequence in the N2B-domain (N2B_us) by protein kinases, PKA or PKG, reduces titin-based passive stiffness by increasing the bending rigidity of this elastic domain. PKG-mediated titin phosphorylation can be induced by sildenafil (phosphodiesterase-5 inhibitor) in a dog model of diastolic heart failure, thus lowering pathologically increased passive stiffness. Furthermore, oxidative-stress conditions promote the formation of disulfide bridges within the N2B_us, which increases titin-based stiffness.

Conclusions: 

The acute adjustment of titin stiffness by phosphorylation or disulfide bonding may have an equal or greater role in myocardial stiffness modulation than long-term stiffness adjustment through titin-isoform switching. Novel evidence also suggests (de)phosphorylation of the titin N2B_us is involved in cardiac hypertrophic signaling.