Rapid Disuse Atrophy of Diaphragm Fibers in Mechanically Ventilated Humans
Sanford Levine, M.D., Taitan Nguyen, B.S.E., Nyali Taylor, M.D., M.P.H., Michael E. Friscia, M.D., Murat T. Budak, M.D., Ph.D., Pamela Rothenberg, B.A., Jianliang Zhu, M.D., Rajeev Sachdeva, M.D., Seema Sonnad, Ph.D., Larry R. Kaiser, M.D., Neal A. Rubinstein, M.D., Ph.D., Scott K. Powers, Ph.D., Ed.D., and Joseph B. Shrager, M.D.
Background The combination of complete diaphragm inactivityand mechanical ventilation (for more than 18 hours) elicitsdisuse atrophy of myofibers in animals. We hypothesized thatthe same may also occur in the human diaphragm.
Methods We obtained biopsy specimens from the costal diaphragmsof 14 brain-dead organ donors before organ harvest (case subjects)and compared them with intraoperative biopsy specimens fromthe diaphragms of 8 patients who were undergoing surgery foreither benign lesions or localized lung cancer (control subjects).Case subjects had diaphragmatic inactivity and underwent mechanicalventilation for 18 to 69 hours; among control subjects diaphragmaticinactivity and mechanical ventilation were limited to 2 to 3hours. We carried out histologic, biochemical, and gene-expressionstudies on these specimens.
Results As compared with diaphragm-biopsy specimens from controls,specimens from case subjects showed decreased cross-sectionalareas of slow-twitch and fast-twitch fibers of 57% (P=0.001)and 53% (P=0.01), respectively, decreased glutathione concentrationof 23% (P=0.01), increased active caspase-3 expression of 100%(P=0.05), a 200% higher ratio of atrogin-1 messenger RNA (mRNA)transcripts to MBD4 (a housekeeping gene) (P=0.002), and a 590%higher ratio of MuRF-1 mRNA transcripts to MBD4 (P=0.001).
Conclusions The combination of 18 to 69 hours of complete diaphragmaticinactivity and mechanical ventilation results in marked atrophyof human diaphragm myofibers. These findings are consistentwith increased diaphragmatic proteolysis during inactivity.
Source Information
From the Department of Surgery (S.L., T.N., N.T., M.E.F., M.T.B., P.R., J.Z., S.S., L.R.K., J.B.S.), the Department of Cell and Developmental Biology (N.A.R.), and the Pennsylvania Muscle Institute (S.L., M.T.B., N.A.R., J.B.S.), University of Pennsylvania; the Gift of Life Donor Program (S.L.); Medical Research, Surgical, and Laboratory Medicine Services, Department of Veterans Affairs Medical Center (S.L., T.N., R.S., J.B.S.) — all in Philadelphia; and the Center for Exercise Science, University of Florida, Gainesville (S.K.P.).
Address reprint requests to Dr. Levine at 1495 Wesleys Run, Gladwyne, PA 19035, or at sdlevine{at}mail.med.upenn.edu.
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