Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Abstract

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.

Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

“…If true in humans, this could have the impact of requiring a greater neuronal stimulation to sustain a given Pdi during tidal breathing, possibly contributing to elevations of diaphragm muscle activation seen during resting breathing in COPD (11). The changes in twitch force observed in some studies are also consistent with the observation from Ottenheijm et al (62) that fibers from patients with mild to moderate COPD have lower Ca 2ϩ sensitivities in both type I and IIA fibers. This has recently been confirmed by the same group in another set of mild to moderate COPD patients (86).…”

“…The mechanisms for these changes and the impact they might have on normal function are not entirely clear, but they probably contribute to accompanying improvements in contractile efficiency that have also been observed (84). Shifts in the sarcomeric Ca 2ϩ ATPase isoforms (62) to slower, more oxidative isoforms parallel the shifts to slow MHCs, as observed by Nguyen et al (56). This response could also contribute to improvements in efficiency of contraction.…”

“…In contrast, Stubbings et al (84) found no such changes in specific force of isolated biopsy specimens in any fibers studied. There are no clear differences that can account for the opposing findings of Stubbings et al (84) and Ottenheijm et al (62). Although Levine et al (40) observed losses of specific force in a small sample of patients in the most severe category of COPD, Ottenheijm et al (64) and Stubbings et al (84) analyzed patients with similar, wide ranges of relatively modest lung dysfunction.…”

“…For example, in control rodent diaphragms, type I fibers demonstrate a 50% loss of specific force compared with fast fibers (26), due in part to reductions in myosin content. Ottenheijm et al (62) have shown that essentially all of the loss of single-fiber specific force in human diaphragm from patients with moderate disease can be accounted for by reductions in myosin content, although whether this applies to patients with severe disease is still unclear. It is debatable whether a loss of specific force in exchange for a gain in aerobic function is always a positive adaptation to all varieties of obstructive disease.…”

“…However, the rate of isometric force development is reduced in type I fibers (84), and the rate of force redevelopment following shortening (a measure of the rate of cross-bridge kinetics) is reduced in both type I and IIA fibers (62). The mechanisms for these changes and the impact they might have on normal function are not entirely clear, but they probably contribute to accompanying improvements in contractile efficiency that have also been observed (84).…”