Shortening of Titin's Elastic Tandem Ig Segment Leads to Cardiac Hypertrophy and Diastolic Dysfunction

Abstract

Diastolic dysfunction is a poorly understood but clinically pervasive syndrome. Titin is the main determinant of cellular passive stiffness. However, the physiological role that titin's tandem Ig segment plays in stiffness generation and whether shortening this segment is sufficient to cause diastolic dysfunction needs to be established by performing studies at a wide range of organizational levels (skinned cells to the in vivo LV chamber). We produced a novel KO model by deleting nine immunoglobulin(Ig)-like domains from the proximal tandem Ig segment (Ig 3-11) of titin's spring region (IG KO). Exon microarray analysis revealed no adaptations in titin splicing, while novel phospho-specific antibodies did not detect changes in titin phosphorylation. Passive myocyte stiffness was increased in the KO and immunoelectron microscopy revealed increased extension of the remaining titin spring segments as the likely underlying mechanism. Diastolic stiffness was increased at the tissue and organ levels; myocardial stiffness studies did not detect changes in extracellular matrix based passive stiffness, supporting a titin-based mechanism. IG KO mice have a reduced exercise tolerance and develop LV hypertrophy that is associated with a marked increase in expression of hypertrophy-associated four and a half LIM proteins (FHL). These findings suggest that titin-based stiffness plays a role in diastolic dysfunction and hypertrophic signaling and that increased titin-based passive stiffness is sufficient to cause diastolic dysfunction with exercise intolerance and LV hypertrophy.