Published ahead of print on April 5, 2007, doi:10.1164/rccm.200701-020PP Am. J. Respir. Crit. Care Med., Volume 175, Number 12, June 2007, 1233-1240 A more recent version of this article appeared on June 15, 2007
Submitted on January 3, 2007 Diaphragm Muscle Fiber Dysfunction in COPD:Towards a Pathophysiological ConceptCoen A.C. Ottenheijm1*,1 Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Radboud University Nijmegen Medical Centre, Institute for Fundamental and Clinical Human Movement Sciences, Nijmegen, The Netherlands; Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA, USA, 2 Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Radboud University Nijmegen Medical Centre, Institute for Fundamental and Clinical Human Movement Sciences, Nijmegen, The Netherlands, 3 Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Radboud University Nijmegen Medical Centre, Institute for Fundamental and Clinical Human Movement Sciences, Nijmegen, The Netherlands * To whom correspondence should be addressed. E-mail: c.ottenheijm{at}long.umcn.nl.
Inspiratory muscle weakness in patients with COPD is of major clinical relevance; maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered of pathologic nature. Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single fiber level is associated with loss of myosin content. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. The current Pulmonary Perspective postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in COPD patients. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities. Therefore, investigating in vivo diaphragm function in mild-to-moderate COPD should be the focus of future research. Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings show promise for the use of proteasome inhibitors in syndromes associated with muscle wasting, such as the diaphragm in COPD. Key words: COPD, diaphragm, muscle wasting, contractile dysfunction, titin
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