Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD

Abstract

To assess the effect of severe chronic obstructive pulmonary disease (COPD) on the ability of human diaphragmatic myofibers to aerobically generate ATP relative to ATP utilization, we obtained biopsy specimens of the costal diaphragm from seven patients with severe COPD (mean +/- SE; age 56 +/- 1 yr; forced expiratory volume in 1 s 23 +/- 2% predicted; residual volume 267 +/- 30% predicted) and seven age-matched control subjects. We categorized all fibers in these biopsies by using standard techniques, and we carried out the following quantitative histochemical measurements by microdensitometry: 1) succinate dehydrogenase (SDH) activity as an indicator of mitochondrial oxidative capacity and 2) calcium-activated myosin ATPase (mATPase) activity, the ATPase that represents a major portion of ATP consumption by contracting muscle. We noted the following: 1) COPD diaphragms had a larger proportion of type I fibers, a lesser proportion of type IIax fibers, and the same proportion of type IIa fibers as controls. 2) SDH activities of each of the fiber types were higher in COPD than control diaphragms (P < 0.0001); the mean increases (expressed as percent of control values) in types I, IIa, and IIax were 84, 114, and 130%, respectively. 3) COPD elicited no change in mATPase activity of type I and IIa fibers, but mATPase decreased in type IIax fibers (P = 0.02). 4) Mitochondrial oxidative capacity relative to ATP demand (i.e., SDH/mATPase) was higher (P = 0.03) in each of the fiber types in COPD diaphragms than in controls. These results demonstrate that severe COPD elicits an increase in aerobic ATP generating capacity relative to ATP utilization in all diaphragmatic fiber types as well as the previously described fast-to-slow fiber type transformation (Levine S, Kaiser L, Leferovich J, and Tikunov B, N Engl J Med 337: 1799-1806, 1997).

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

“…Sanchez et al (78) reported a general loss in diameter of both type I and type II fibers. This was also addressed by Levine et al (37) and in the recent work of Stubbings et al (84). Both report significant reductions (41% in Ref.…”

“…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.…”

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective

“…In the COPD patient group, FOXO‐1 protein expression was higher in limb muscles than in respiratory muscles, while this difference was not found in controls 46. Interestingly, the respiratory muscles of COPD patients show an opposite fibre type shift compared with limb muscles, that is, towards more type I fibres 47, 48. This will have implications for the expression levels of constituents of atrophy signalling pathways 22, 49.…”

Differential effects of emphysema on skeletal muscle fibre atrophy in hamsters

“…As indicated by LEVINE et al [28], differences may exist between the adaptation of the diaphragm to EMP in animals and the human with COPD. In general, it appears that the hamster diaphragm adapts by increasing the CSA of both type I and II fibres without fibre transformation, whereas the human diaphragm adapts with type I fibre atrophy that may or may not be associated with a type II to I fibre transformation.…”