Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness.
BACKGROUND
Titin contains a molecular spring segment that underlies passive myocardial stiffness. Myocardium coexpresses titin isoforms with molecular spring length variants and, consequently, distinct stiffness characteristics: the stiff N2B isoform (short spring) and more compliant N2BA isoform (long spring). We tested whether changes in titin isoform expression occur in the diastolic dysfunction that accompanies heart failure.


RESULTS
We used the tachycardia-induced dilated cardiomyopathy canine model (4-week pacing) and found that control myocardium coexpresses the N2B and N2BA isoforms at similar levels, whereas in dilated cardiomyopathy the expression ratio had shifted, without affecting the amount of total titin, toward more prominent N2B expression. This shift was accompanied by elevated titin-based passive muscle stiffness. Pacing also resulted in significant upregulation of obscurin, an approximately 800-kDa elastic protein with several signaling domains.


CONCLUSIONS
Coexpression of titin isoforms with distinct mechanical properties allows modulation of passive stiffness via adjustment of the isoform expression ratio. The canine pacing-induced heart failure model uses this mechanism to increase myocardial stiffness. Thus, changes in titin isoform expression may play a role in diastolic dysfunction in heart failure.
Wu
Yiming
Y
Department VCAPP, Washington State University, Pullman 99164-6520, USA.
Bell
Stephen P
SP
Trombitas
Karoly
K
Witt
Christian C
CC
Labeit
Siegfried
S
LeWinter
Martin M
MM
Granzier
Henk
H
D000818:Animals; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D064211:Connectin; D046508:Culture Techniques; D003971:Diastole; D004285:Dogs; D004548:Elasticity; D016253:Microscopy, Immunoelectron; D009124:Muscle Proteins / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure
D064211:Connectin; D009124:Muscle Proteins; D020033:Protein Isoforms; D011494:Protein Kinases