Proteasome Inhibition Alleviates Muscle Damage as Induced by Prolonged Moderate Compression

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PURPOSE: Deep pressure ulcer represents a considerable clinical problem resulting in heavy burdens on health caregivers and patients. The cellular and molecular mechanisms responsible for development of deep pressure ulcer remain to be elucidated. The present study tested the hypothesis that ubiquitin proteasome is involved in the signaling mechanism of muscle damage in pressure-induced deep tissue injury. METHODS: Adult Sprague Dawley rats (n=8) were subjected to an experimental compression model to induce deep tissue injury. The tibialis region of right hind limb of animals was exposed to 100 mmHg of static pressure for six hours per day for two consecutive days. In a subsequent experiment, 10 mg/kg of MG132 or DMSO (vehicle control) was administrated prior to the compression procedure by i.p. injection (n=4/group). The compression pressure was continuously monitored by a three-axial force transducer equipped in the compression indentor. The left hind limb served as intra-animal uncompressed control. Muscle tissues underneath the compressed region were collected. The tissue histology was examined by hematoxylin and eosin staining. Protein abundance of ubiquitin and MAFbx/atrogin-1 was determined by Western blotting. Proteasome activity was examined by measuring the 20S proteasome activity. RESULTS: In the compressed muscle, pathologic histology including loss of angular shape contour of cross-sectional myofibers, increased proportion of interstitial space, increment of nuclei number in the interstitial space, and internalization of peripherally located nuclei in myofibers were demonstrated. The 20S proteasome activity and protein abundance of ubiquitin and MAFbx/atrogin-1 were significantly increased in the compressed muscle when compared to control muscle. The administration of MG132 was found to be effective in alleviating the compression-induced pathologic histology in muscle. The increases in ubiquitin, MAFbx/atrogin-1, and 20S proteasome activity that were observed in muscle after compression were apparently absent in MG132-treated muscle following compression. CONCLUSIONS: Our data suggest that muscle ubiquitin proteasome pathway plays an important role in the pathogenesis of pressure-induced deep tissue injury. Supported by Hong Kong PolyU Research Fund A-PH69 and G-U645