Diaphragm dysfunction in chronic obstructive pulmonary disease.
BACKGROUND
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.


OBJECTIVE
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 FEV(1) % 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.
Ottenheijm
Coen A C
CA
Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Heunks
Leo M A
LM
Sieck
Gary C
GC
Zhan
Wen-Zhi
WZ
Jansen
Suzanne M
SM
Degens
Hans
H
de Boo
Theo
T
Dekhuijzen
P N Richard
PN
D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D009994:Osmolar Concentration; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology*; D012518:Sarcomeres / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D009124:Muscle Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains; D002118:Calcium