This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200502-262OCv1 172/2/200    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ottenheijm, C. A. C. Articles by Dekhuijzen, P. N. R. Search for Related Content PubMed PubMed Citation Articles by Ottenheijm, C. A. C. Articles by Dekhuijzen, P. N. R.

Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Department of Pulmonary Diseases, Epidemiology, and Biostatistics, and Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre; Department of Cell Biology, Faculty of Science, Radboud University Nijmegen, Nijmegen, The Netherlands; and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota

Correspondence and requests for reprints should be addressed to P. N. Richard Dekhuijzen, M.D., Ph.D., Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: r.dekhuijzen{at}long.umcn.nl

Rationale: Hypercapnic respiratory failure because of inspiratory muscle weakness is the most important cause of death in chronic obstructive pulmonary disease (COPD). However, the pathophysiology of failure of the diaphragm to generate force in COPD is in part unclear. Objectives: The present study investigated contractile function and myosin heavy chain content of diaphragm muscle single fibers from patients with COPD. Methods: Skinned muscle fibers were isolated from muscle biopsies from the diaphragm of eight patients with mild to moderate COPD and five patients without COPD (mean FEV₁ % predicted, 70 and 100%, respectively). Contractile function of single fibers was assessed, and afterwards, myosin heavy chain content was determined in these fibers. In diaphragm muscle homogenates, the level of ubiquitin-protein conjugation was determined. Results: Diaphragm muscle fibers from patients with COPD showed reduced force generation per cross-sectional area, and reduced myosin heavy chain content per half sarcomere. In addition, these fibers had decreased Ca²⁺ sensitivity of force generation, and slower cross-bridge cycling kinetics. Our observations were present in fibers expressing slow and 2A isoforms of myosin heavy chain. Ubiquitin-protein conjugation was increased in diaphragm muscle homogenates of patients with mild to moderate COPD. Conclusions: Early in the development of COPD, diaphragm fiber contractile function is impaired. Our data suggest that enhanced diaphragm protein degradation through the ubiquitin-proteasome pathway plays a role in loss of contractile protein and, consequently, failure of the diaphragm to generate force.

Key Words: contractility • myosin • single fiber • ubiquitin

This article has been cited by other articles:

				D. McCool, N. Ayas, R. Brown, S. H. Loring, L. M.A. Heunks, R. P.N. Dekhuijzen, E. Fan, D. M. Needham, F. Leo, L. Spaggiari, et al. Mechanical ventilation and disuse atrophy of the diaphragm. N. Engl. J. Med., July 3, 2008; 359(1): 89 - 90. [Full Text] [PDF]

				H. W. H. van Hees, Y.-P. Li, C. A. C. Ottenheijm, B. Jin, C. J. C. Pigmans, M. Linkels, P. N. R. Dekhuijzen, and L. M. A. Heunks Proteasome inhibition improves diaphragm function in congestive heart failure rats Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1260 - L1268. [Abstract] [Full Text] [PDF]

				A. K. Stubbings, A. J. Moore, M. Dusmet, P. Goldstraw, T. G. West, M. I. Polkey, and M. A. Ferenczi Physiological properties of human diaphragm muscle fibres and the effect of chronic obstructive pulmonary disease J. Physiol., May 15, 2008; 586(10): 2637 - 2650. [Abstract] [Full Text] [PDF]

				J. Ochala and L. Larsson Effects of a preferential myosin loss on Ca2+ activation of force generation in single human skeletal muscle fibres Exp Physiol, April 1, 2008; 93(4): 486 - 495. [Abstract] [Full Text] [PDF]

				R. C. J. Langen and A. M. W. J. Schols Inflammation: friend or foe of muscle remodelling in COPD? Eur. Respir. J., October 1, 2007; 30(4): 605 - 607. [Full Text] [PDF]

				C. A. C. Ottenheijm, G. J. Jenniskens, M. C. P. Geraedts, T. Hafmans, L. M. A. Heunks, T. H. van Kuppevelt, and P. N. R. Dekhuijzen Diaphragm dysfunction in chronic obstructive pulmonary disease: a role for heparan sulphate? Eur. Respir. J., July 1, 2007; 30(1): 80 - 89. [Abstract] [Full Text] [PDF]

				H. Degens, A. K. Swisher, Y. F. Heijdra, P. M. Siu, P. N. Richard Dekhuijzen, and S. E. Alway Apoptosis and Id2 expression in diaphragm and soleus muscle from the emphysematous hamster Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R135 - R144. [Abstract] [Full Text] [PDF]

				H. W. H. van Hees, H. F. M. van der Heijden, C. A. C. Ottenheijm, L. M. A. Heunks, C. J. C. Pigmans, F. W. A. Verheugt, R. M. H. J. Brouwer, and P. N. R. Dekhuijzen Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H819 - H828. [Abstract] [Full Text] [PDF]

				C. A. C. Ottenheijm, L. M. A. Heunks, and P. N. R. Dekhuijzen Diaphragm Muscle Fiber Dysfunction in Chronic Obstructive Pulmonary Disease: Toward a Pathophysiological Concept Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1233 - 1240. [Abstract] [Full Text] [PDF]

				A. L. Ries, G. S. Bauldoff, B. W. Carlin, R. Casaburi, C. F. Emery, D. A. Mahler, B. Make, C. L. Rochester, R. ZuWallack, and C. Herrerias Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines Chest, May 1, 2007; 131(5_suppl): 4S - 42S. [Abstract] [Full Text] [PDF]

				C. A. C. Ottenheijm, L. M. A. Heunks, Y.-P. Li, B. Jin, R. Minnaard, H. W. H. van Hees, and P. N. R. Dekhuijzen Activation of the Ubiquitin-Proteasome Pathway in the Diaphragm in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 2006; 174(9): 997 - 1002. [Abstract] [Full Text] [PDF]

				L. M. Fabbri, F. Luppi, B. Beghe, and K. F. Rabe Update in chronic obstructive pulmonary disease 2005. Am. J. Respir. Crit. Care Med., May 15, 2006; 173(10): 1056 - 1065. [Full Text] [PDF]

				H. A. C. van Helvoort, Y. F. Heijdra, L. M. A. Heunks, P. L. M. Meijer, W. Ruitenbeek, H. M. H. Thijs, and P. N. R. Dekhuijzen Supplemental Oxygen Prevents Exercise-induced Oxidative Stress in Muscle-wasted Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 15, 2006; 173(10): 1122 - 1129. [Abstract] [Full Text] [PDF]

				C. A. C. Ottenheijm, L. M. A. Heunks, T. Hafmans, P. F. M. van der Ven, C. Benoist, H. Zhou, S. Labeit, H. L. Granzier, and P. N. R. Dekhuijzen Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 527 - 534. [Abstract] [Full Text] [PDF]

				R. B. Gorman, D. K. McKenzie, J. E. Butler, J. F. Tolman, and S. C. Gandevia Diaphragm Length and Neural Drive after Lung Volume Reduction Surgery Am. J. Respir. Crit. Care Med., November 15, 2005; 172(10): 1259 - 1266. [Abstract] [Full Text] [PDF]