Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans.
BACKGROUND
The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm.


METHODS
We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects). Case subjects had diaphragmatic inactivity and underwent mechanical ventilation for 18 to 69 hours; among control subjects diaphragmatic inactivity and mechanical ventilation were limited to 2 to 3 hours. We carried out histologic, biochemical, and gene-expression studies on these specimens.


RESULTS
As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively, decreased glutathione concentration of 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 diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibers. These findings are consistent with increased diaphragmatic proteolysis during inactivity.
Levine
Sanford
S
Department of Surgery, University of Pennsylvania, USA. sdlevine@mail.med.upenn.edu
Nguyen
Taitan
T
Taylor
Nyali
N
Friscia
Michael E
ME
Budak
Murat T
MT
Rothenberg
Pamela
P
Zhu
Jianliang
J
Sachdeva
Rajeev
R
Sonnad
Seema
S
Kaiser
Larry R
LR
Rubinstein
Neal A
NA
Powers
Scott K
SK
Shrager
Joseph B
JB
D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D001926:Brain Death; D016022:Case-Control Studies; D003964:Diaphragm / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009133:Muscular Atrophy / Q000209:etiology* / Q000473:pathology; D010369:Pectoralis Muscles / Q000033:anatomy & histology; D012333:RNA, Messenger / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D014019:Tissue Donors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases