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.
Keywords: contractility, myosin, single fiber, ubiquitin
PMCID: PMC2718467 PMID: 15849324 doi: 10.1164/rccm.200502-262OC

Skeletal muscle myopathy is a well-known side-effect of systemically administered corticosteroids. In recent years renewed attention is being paid to the involvement of the respiratory muscles and its consequent significance in pulmonary patients. Two different clinical patterns of steroid-induced muscular changes are known. In acute myopathy and atrophy after short term treatment with high doses of steroids, generalized muscle atrophy and rhabdomyolysis occur, including the respiratory muscles. Chronic steroid myopathy, occurring after prolonged treatment with moderate doses, is characterized by the gradual onset of proximal limb muscle weakness and may be accompanied by reduced respiratory muscle force. Animal studies demonstrated diaphragmatic myopathy and atrophy similar to the alterations in peripheral skeletal muscles. Fluorinated steroids induced selective type IIb (fast-twitch glycolytic) fibre atrophy, resulting in changes in contractile properties of the diaphragm. Non-fluorinated steroids may also induce histological, biochemical and functional alterations in the diaphragm. Observations in patients with collagen vascular disorders and with asthma and chronic obstructive pulmonary disease (COPD) underline the potential hazards of treatment with corticosteroids to respiratory muscle structure and function.
PMID: 1426209

Two women with connective tissue disease developed a characteristic steroid-induced myopathy. Reduced maximal transrespiratory pressures indicated reduced respiratory muscle strength. Gradual steroid dosage tapering resulted in prompt clinical improvement and marked increases in respiratory muscle strength, maximal inspiratory pressure increasing by 33 percent in one patient and by 70 percent in the other. This reversible steroid-induced respiratory muscle weakness may be of great significance in reconsidering long-term steroid therapy in patients with underlying lung disease.
PMID: 2707077 DOI: 10.1378/chest.95.5.1160

PURPOSE: The authors determined the degree of respiratory and peripheral muscle weakness in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Differences in severity of muscle weakness among muscle groups may provide treatment options, such as selective muscle training, to adapt the exercise prescription in pulmonary rehabilitation programs. In addition, this information may add to the knowledge on the mechanisms of muscle weakness.
METHODS: Respiratory and peripheral muscle force were quantified in 22 healthy elderly subjects and 40 consecutive COPD patients (forced expiratory volume in 1 second, percent of predicted value [% pred] 41 +/- 19; transfer factor for carbon monoxide, % pred 47 +/- 26) admitted to a pulmonary rehabilitation program. Lung function, diffusing capacity, isometric force of four peripheral muscle groups (handgrip, elbow flexion, shoulder abduction, and knee extension), neck flexion force, and maximal inspiratory and expiratory pressures were measured.
RESULTS: Patients had reduced respiratory muscle strength (mean 64% of control subjects' value [% control]) and peripheral muscle strength (mean 75% control) compared to normal subjects. Inspiratory muscle strength (59 +/- 18% control) was significantly lower than expiratory muscle strength (69 +/- 25% control) and peripheral muscle strength (P < 0.01). Neck flexion force (80 +/- 19% control) was better preserved than maximal inspiratory pressure and shoulder abduction force (70 +/- 15% control, P < 0.01). Handgrip force (78 +/- 16% control) and elbow flexion force (78 +/- 14% control) were significantly less affected than shoulder abduction force (70 +/- 15% control, P < 0.01). Finally, shoulder abduction force and knee-extension force (72 +/- 24% control) were not significantly different.
CONCLUSIONS: Muscle weakness in stable COPD patients does not affect all muscles to a similar extent. Inspiratory muscle force is affected more than peripheral muscle force, whereas proximal upper limb muscle strength was impaired more than distal upper limb muscle strength.
PMID: 11144041 DOI: 10.1097/00008483-200011000-00004

RATIONALE: It is not known if abnormal dynamic respiratory mechanics actually limit exercise in patients with mild chronic obstructive pulmonary disease (COPD). We reasoned that failure to increase peak ventilation and Vt in response to dead space (DS) loading during exercise would indicate true ventilatory limitation to exercise in mild COPD.
OBJECTIVES: To compare the effects of DS loading during exercise on ventilation, breathing pattern, operating lung volumes, and dyspnea intensity in subjects with mild symptomatic COPD and age- and sex-matched healthy control subjects.
METHODS: Twenty subjects with Global Initiative for Chronic Obstructive Lung Disease stage I COPD and 20 healthy subjects completed two symptom-limited incremental cycle exercise tests, in randomized order: unloaded control and added DS of 0.6 L.
MEASUREMENTS AND MAIN RESULTS: Peak oxygen uptake and ventilation were significantly lower in COPD than in health by 36% and 41%, respectively. With added DS compared with control, both groups had small decreases in peak work rate and no significant increase in peak ventilation. In health, peak Vt and end-inspiratory lung volume increased significantly with DS. In contrast, the COPD group failed to increase peak end-inspiratory lung volume and had a significantly smaller increase in peak Vt during DS. At 60 W, a 50% smaller increase in Vt (P < 0.001) in response to added DS in COPD compared with health was associated with a greater increase in dyspnea intensity (P = 0.0005).
CONCLUSIONS: These results show that the respiratory system reached or approached its physiologic limit in mild COPD at a lower peak work rate and ventilation than in healthy participants. Clinical trial registered with www.clinicaltrials.gov (NCT 00975403).
PMID: 23590271 DOI: 10.1164/rccm.201211-1970OC