Human Diaphragm Remodeling Associated with Chronic Obstructive Pulmonary Disease

Abstract

Diaphragm remodeling associated with chronic obstructive pulmonary disease (COPD) consists of a fast-to-slow fiber type transformation as well as adaptations within each fiber type. To try to explain disparate findings in the literature regarding the relationship between fiber type proportions and FEV1, we obtained costal diaphragm biopsies on 40 subjects whose FEV1 ranged from 118 to 16% of the predicted normal value. First, we noted that our exponential regression model indicated that changes in FEV1 can account for 72% of the variation in the proportion of Type I fibers. Second, to assess the impact of COPD on diaphragm force generation, we measured maximal specific force generated by single permeabilized fibers prepared from the diaphragms of two patients with normal pulmonary function tests and two patients with severe COPD. We noted that fibers prepared from the diaphragms of severe COPD patients generated a lower specific force than control fibers (p < 0.001) and Type I fibers generated a lower specific force than Type II fibers (p < 0.001). Our finding of an exponential relationship between the proportion of Type I fibers and FEV1 accounts for discrepancies in the literature. Moreover, our single-fiber results suggest that COPD-associated diaphragm remodeling decreases diaphragmatic force generation by adaptations within each fiber type as well as by fiber type transformations.

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

“…Furthermore, the increase in type I fiber populations is clearly related to the severity of disease and the extent of hyperinflation, as shown in Fig. 2, C and D, from Levine et al (40).…”

“…The largest exceptions to this are the work of Lewis et al (43), who showed reductions in in vitro specific force of Ͼ20%, and Huenks et al (32), who demonstrated reductions of ϳ14%. In human studies of isolated fibers from biopsy specimens, two groups, Levine et al (40) and Ottenheijm et al (64), have found significant reductions in specific force in individual costal diaphragm fibers (Table 2), an observation recently confirmed in another group of COPD patients by these authors (86 1, increase; 2, decrease; TLC, total lung capacity; FRC, functional residual capacity;…”

“…Multiple studies from several laboratories have shown statistically significant increases in the relative proportions of type I fibers in the costal diaphragm (18,37,38,40,84), with two of the laboratories demonstrating a strong correlative relationship of the proportion of type I oxidative fibers with deterioration of lung function (40,84). Figure 2, A and B, illustrates the contrasting differences in fiber populations in control vs. severe emphysema patients.…”

“…D: changes in the area fraction, i.e., the proportion of the total cross-sectional area of the diaphragm taken up by type I fibers, as a function of increasing hyperinflation. Symbols and lines are as defined in C. [A and B, reproduced from Levine et al (37); C and D, reproduced from Levine et al (40) with permission from American Thoracic Society. ] rapid limb growth in all organisms and are important in preventing length-induced injuries during growth phases.…”

“…These results are complimented by analysis of MHC expression (Table 2). A general consensus finds a large increase in the MHC I isoform, corresponding to the myosin predominant in type I fibers (38,40,54,77) and relative decreases in MHC IIA (38) and IIX (38,77) isoforms. In addition, Nguyen et al (57) have shown that the proportion of fibers in the diaphragm that contain MHC I isoforms is significantly increased, whereas the proportion expressing IIA or IIB (probably IIX) isoforms is reduced.…”