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Published ahead of print on December 9, 2005, doi:10.1164/rccm.200507-1056OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 5, March 2006, 527-534

A more recent version of this article appeared on March 1, 2006
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Submitted on July 8, 2005
Accepted on December 6, 2005

Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Coen A.C. Ottenheijm1, Leo M.A. Heunks1, Theo Hafmans2, Peter F.M. van der Ven3, Caroline Benoist4, Honghui Zhou4, Siegfried Labeit5, Henk L Granzier4, and P.N. Richard Dekhuijzen1*

1 Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 2 Biochemistry at NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 3 Department of Molecular Cell Biology, University of Bonn, Bonn, Germany, 4 Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington, USA, 5 Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington, USA; Institut fur Anasthesiologie und Operative Intensivmedizin, Universitatsklinikum Mannheim, Mannheim, Germany

* To whom correspondence should be addressed. E-mail: r.dekhuijzen{at}long.umcn.nl.

RATIONALE Recently, we have shown that Ca2+-activated force generation in diaphragm single fibers is impaired in patients with mild-to-moderate COPD. For optimal active force generation, the passive-elasticity provided by titin is indispensable. OBJECTIVES In the present study we determined the passive tension-length relation of single fibers of patients with mild-to-moderate COPD, hypothesizing that passive-elastic properties of diaphragm fibers are compromised. METHODS Passive tension-length relations were determined in diaphragm fibers from patients with and without COPD (predicted mean FEV1 76% and 102%, respectively). In diaphragm homogenates titin expression at the protein level by gel-electrophoresis and at the transcript level by using a novel titin exon microarray were studied. RESULTS Diaphragm fibers from patients with COPD generate less passive tension upon stretch. Titin content in the diaphragm was not different between patients with and without COPD. However, titin exon transcript studies revealed upregulation of 7 exons, which code for spring elements in the elastic PEVK segment (titin-segment rich in proline (P), glutamate (E), valine (V), and lysine (K)). Immuno-fluorescence analysis indicated elevated protein expression of the upregulated splice variant in the COPD diaphragm. Simulation studies on titin molecules including the aminoacids encoded by the 7 upregulated exons predicted reduced passive tension generation upon molecule stretch. CONCLUSIONS Passive tension generation of diaphragm single fibers is reduced in patients with COPD. Our results suggest that alternative splicing of the titin gene, resulting in increased length of the elastic PEVK segment, is involved. Interestingly, these changes occur already in patients with mild-to-moderate COPD (GOLD I/II).
Key words: transcript studies, diaphragm, titin, COPD, single fiber stiffness




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