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Published ahead of print on December 9, 2005, doi:10.1164/rccm.200507-1056OC
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 527-534, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200507-1056OC

Original Article

Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Coen A. C. Ottenheijm, Leo M. A. Heunks, Theo Hafmans, Peter F. M. van der Ven, Caroline Benoist, Honghui Zhou, Siegfried Labeit, Henk L. Granzier and P. N. Richard Dekhuijzen

Department of Pulmonary Diseases, Biochemistry at NCMLS, Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Molecular Cell Biology, University of Bonn, Bonn; Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany; and Department of Veterinaryand Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington

Correspondence and requests for reprints should be addressed to P.N. Richard Dekhuijzen, M.D., Ph.D., Department of Pulmonary Diseases, 454 Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. 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 chronic obstructive pulmonary disease (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 relations 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 was studied at the protein level by gel electrophoresis and at the transcript level by using a novel titin exon microarray.

Results: Diaphragm fibers from patients with COPD generate less passive tension on stretch. Titin content in the diaphragm did not differ between patients with and without COPD. However, titin exon transcript studies revealed up-regulation of seven exons, which code for spring elements in the elastic segment rich in proline, glutamate, valine, and lysine. Immunofluorescence analysis indicated elevated protein expression of the up-regulated splice variant in the COPD diaphragm. Simulation studies on titin molecules including the amino acids encoded by the seven up-regulated exons predicted reduced passive-tension generation on 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 segment rich in proline, glutamate, valine, and lysine, is involved. Interestingly, these changes occur already in patients with mild to moderate COPD.

Key Words: chronic obstructive pulmonary disease • diaphragm • single-fiber stiffness • titin • transcript studies




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