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1 Surgical and Research Services, Veterans Affairs Medical Center, Philadelphia, PA, USA; Department of Surgery and Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2 Department of Surgery and Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
3 National Eye Institute, National Institutes of Health, Bethesda, MD, USA
4 Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: sdlevine{at}mail.med.upenn.edu.
We have previously demonstrated that human diaphragm remodeling elicited by severe COPD is characterized by a fast-to-slow myosin heavy chain isoform transformation. To test the hypothesis that COPD-induced diaphragm remodeling also elicits a fast-to-slow isoform shift in the sarcoendoplasmic reticulum calcium ATPase (SERCA)-the other major ATPase in skeletal muscle-we obtained intra-operative biopsies of the costal diaphragm from 10 severe COPD patients and 10 control subjects. We then used isoform specific monoclonal antibodies to characterize diaphragm fibers with respect to the expression of SERCA isoforms. Compared to control diaphragms, COPD diaphragms exhibited a 63% decrease in fibers expressing only fast SERCA (i.e., SERCA1 (p<0.001)), a 190% increase in fibers containing both fast and slow SERCA isoforms (p<0.01), and a 19% increase (p<0.05) in fibers expressing only the slow SERCA isoform (i.e., SERCA2). Additionally, immunoblot experiments carried out on diaphragm homogenates indicated that COPD diaphragms expressed only one-third the SERCA1 content noted in control diaphragms; in contrast, COPD and control diaphragms did not differ with respect to SERCA2 content. The combination of these histological and immunoblot results is consistent with the hypothesis that diaphragm remodeling elicited by severe COPD is characterized by a fast-to-slow SERCA isoform transformation. Moreover, the combination of these SERCA data and our previously reported myosin heavy chain isoform data (Levine et al., Am J Respir Crit Care Med 168:706-713, 2003) suggest that diaphragm remodeling elicited by severe COPD should decrease ATP utilization by the diaphragm.
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