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J Appl Physiol 92: 1205-1213, 2002. First published November 16, 2001; doi:10.1152/japplphysiol.00116.2001
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Vol. 92, Issue 3, 1205-1213, March 2002

Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD

Sanford Levine1,2, Chris Gregory3, Taitan Nguyen1, Joseph Shrager1,2, Larry Kaiser2, Neal Rubinstein2, and Gary Dudley3

1 Medical, Surgical, and Research Services, Philadelphia Veterans Affairs Medical Center, and 2 Departments of Medicine, Surgery, and Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and 3 Department of Exercise Science, University of Georgia, Athens, Georgia 30602

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).

chronic obstructive pulmonary disease; human diaphragm; succinate dehydrogenase; calcium-activated myosin ATPase; mitochondrial oxidative capacity; diaphragmatic fatigue; muscle fatigue


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