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Titin and diaphragm dysfunction in chronic obstructive pulmonary disease.
Coen A C Ottenheijm1, Leo M A Heunks, Theo Hafmans
1Department of Pulmonary Diseases, 454 Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
American Journal of Respiratory and Critical Care Medicine
|December 13, 2005
Summary
Diaphragm muscle fibers in patients with chronic obstructive pulmonary disease (COPD) generate less passive tension due to changes in titin protein. These alterations in titin, a key elastic protein, occur even in mild to moderate COPD.
Area of Science:
- Biophysics
- Muscle Physiology
- Respiratory Medicine
Background:
- Diaphragm muscle force generation is impaired in chronic obstructive pulmonary disease (COPD).
- Titin, a passive elastic protein, is crucial for optimal muscle force.
- Previous research indicated impaired Ca2+-activated force in COPD diaphragm fibers.
Purpose of the Study:
- To investigate the passive-tension-length relationships of single diaphragm muscle fibers in patients with mild to moderate COPD.
- To determine if passive-elastic properties of diaphragm fibers are compromised in COPD.
- To explore the role of titin protein expression and alternative splicing in altered passive mechanics.
Main Methods:
- Passive-tension-length relations were measured in single diaphragm fibers from COPD and control groups.
- Titin protein expression was analyzed using gel electrophoresis.
- Titin gene expression, specifically alternative splicing, was studied using a novel titin exon microarray.
- Immunofluorescence was employed to assess protein expression of specific titin splice variants.
Main Results:
- Diaphragm fibers from COPD patients exhibited reduced passive tension upon stretching.
- Total titin protein content did not differ between COPD and control groups.
- Alternative splicing of the titin gene was observed, with upregulation of seven exons encoding spring elements.
- Elevated protein expression of the upregulated titin splice variant was detected in COPD diaphragms.
- Simulation studies predicted reduced passive tension generation due to the altered titin structure.
Conclusions:
- Passive tension generation is reduced in diaphragm single fibers of patients with mild to moderate COPD.
- Alternative splicing of the titin gene, leading to an elongated elastic segment, is implicated in this functional deficit.
- These titin-related changes are present even in the early stages of COPD, highlighting their significance.