Opposing responses of apoptosis and autophagy to moderate compression in skeletal muscle


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Abstract

Aim:The molecular mechanism that contributes to the pathogenesis of deep pressure ulcer remains to be elucidated. This study tested the hypotheses that: (1) apoptosis and autophagy are activated in compression-induced muscle pathology and (2) apoptotic and autophagic changes precede pathohistological changes in skeletal muscle in response to prolonged moderate compression.Methods:Adult Sprague-Dawley rats were subjected to an experimental model of pressure-induced deep tissue injury. Static pressure of 100 mmHg was applied to an area of 1.5 cm2 over the mid-tibialis region of right limb of rats for one single session of 6-h compression (1D) or two sessions of 6-h compression over two consecutive days with rats sacrificed one day (2D) or immediately after (2D-IM) the compression. The left uncompressed limb served as the intra-animal control. Muscle tissues underneath compression region were collected for analysis.Results:Our histological analysis indicated that pathohistological characteristics including rounding contour of myofibres and massive nuclei accumulation were apparently demonstrated in muscles of 2D and 2D-IM. In contrast, these pathohistological changes were generally not found in muscle following 1D. Apoptotic DNA fragmentation, terminal dUTP nick-end labelling index and caspase-3 protease activity were significantly elevated in compressed muscles of all groups. Caspase-9 enzymatic activity was found to be significantly increased in compressed muscles of 2D and 2D-IM whereas increase in caspase-8 activity was exclusively found in compressed muscle of 1D. According to our immunoblot analysis, FoxO3 was significantly reduced in compressed muscles of all groups whereas Beclin-1 was decreased only in 2D. LC3-I was significantly reduced in compressed muscles of all groups while LC3-II was decreased in 2D and 1D. No significant differences were found in the protein abundance of Akt and phospho-Akt in muscles among all groups.Conclusion:These data demonstrate the opposing responses of apoptosis and autophagy to moderate compression in muscle. Moreover, our findings suggest that cellular changes in apoptosis and autophagy have already taken place in the very early stage in which apparent histopathology has yet to develop in the process of compression-induced muscle pathology.

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