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1 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
2 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
3 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: spowers{at}hhp.ufl.edu.
Prolonged mechanical ventilation (MV) results in diaphragmatic atrophy due, in part, to an increase in proteolysis. These experiments tested the hypothesis that MV-induced diaphragmatic proteolysis is accompanied by increased expression of key components of the ubiquitin-proteasome pathway (UPP). To test this postulate, we investigated the effect of prolonged MV on UPP components and determined the trypsin-like (T-L) and peptidylglutamyl peptide hydrolyzing (PGPH) activities of the 20S proteasome. Adult Sprague-Dawley rats were assigned to either control or 12-hour MV groups (n=7/group). MV animals were anesthetized, tracheostomized, and ventilated with room air for 12 hours. Animals in the control group were acutely anesthetized but not exposed to MV. Compared to controls, MV animals demonstrated increased diaphragmatic mRNA levels of two ubiquitin ligases, Muscle Atrophy F-box (MAFbx/Atrogin-1; +8.3 fold) and Muscle RING Finger-1 (MuRF1; +19.0 fold). However, MV did not alter mRNA levels of 14-kDa ubiquitin conjugating enzyme (E214k), polyubiquitin (pUb), proteasome activating complex PA28 (PA28), or 20S a-subunit 7 (C8). Protein levels of E214k and PA28 were not altered following MV, but C8 levels declined (-17.7%). MV increased diaphragmatic T-L activity (+31%), but did not alter PGPH activity. Finally, compared to controls, MV increased ubiquitin-protein conjugates in both the myofibrillar (+24.9%) and cytosolic (+54.7%) fractions of the diaphragm. These results are consistent with the hypothesis that prolonged MV increases diaphragmatic levels of key components within the UPP and that increases in 20S proteasome activity contribute to MV-induced diaphragmatic proteolysis and atrophy.
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