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, P. N Richard Dekhuijzen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 expressionwas 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.

Original languageEnglish
Pages (from-to)527-534
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume173
Issue number5
DOIs
Publication statusPublished - 1 Mar 2006

Cite this

Ottenheijm, Coen A C ; Heunks, Leo M A ; Hafmans, Theo ; Van Der Ven, Peter F M ; Benoist, Caroline ; Zhou, Honghui ; Labeit, Siegfried ; Granzier, Henk L. ; Dekhuijzen, P. N Richard. / Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. In: American Journal of Respiratory and Critical Care Medicine. 2006 ; Vol. 173, No. 5. pp. 527-534.
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title = "Titin and diaphragm dysfunction in chronic obstructive pulmonary disease",
abstract = "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 expressionwas 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.",
keywords = "Chronic obstructive pulmonary disease, Diaphragm, Single-fiber stiffness, Titin, Transcript studies",
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Ottenheijm, CAC, Heunks, LMA, Hafmans, T, Van Der Ven, PFM, Benoist, C, Zhou, H, Labeit, S, Granzier, HL & Dekhuijzen, PNR 2006, 'Titin and diaphragm dysfunction in chronic obstructive pulmonary disease' American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 5, pp. 527-534. https://doi.org/10.1164/rccm.200507-1056OC

Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. / Ottenheijm, Coen A C; Heunks, Leo M A; Hafmans, Theo; Van Der Ven, Peter F M; Benoist, Caroline; Zhou, Honghui; Labeit, Siegfried; Granzier, Henk L.; Dekhuijzen, P. N Richard.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 173, No. 5, 01.03.2006, p. 527-534.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Titin and diaphragm dysfunction in chronic obstructive pulmonary disease

AU - Ottenheijm, Coen A C

AU - Heunks, Leo M A

AU - Hafmans, Theo

AU - Van Der Ven, Peter F M

AU - Benoist, Caroline

AU - Zhou, Honghui

AU - Labeit, Siegfried

AU - Granzier, Henk L.

AU - Dekhuijzen, P. N Richard

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N2 - 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 expressionwas 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.

AB - 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 expressionwas 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.

KW - Chronic obstructive pulmonary disease

KW - Diaphragm

KW - Single-fiber stiffness

KW - Titin

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