The molecular mechanisms that contribute to the pathogenesis of pressure-induced deep tissue injury are largely unknown. This study tested the hypothesis that oxidative stress and DNA damage signalling mechanism in skeletal muscle are involved in deep tissue injury. Adult Sprague Dawley rats were subject to an experimental protocol to induce deep tissue injury. Two compression cycles with a static pressure of 100 mmHg was applied to an area of 1.5 cm(2) over the mid-tibialis region of right limb of the rats. The left uncompressed limb served as intra-animal control. Muscle tissues underneath compression region were collected for examination. Our analyses indicated that pathohistological characteristics including rounding contour of myofibres and extensive nuclei accumulation were apparently shown in compressed muscles. The elevation of 8OHdG immunopositively stained nuclei indicated the presence of oxidative DNA damage. Increase in oxidative stress was revealed by showing significant elevation of 4HNE and decreases in mRNA abundance of SOD1, catalase and GPx, and protein content of SOD2 in compressed muscles relative to control muscles. Increase in nitrosative stress was demonstrated by significant elevation of nitrotyrosine and NOS2 mRNA content. The activation of tumor suppressor p53 signalling was indicated by the remarkable increases in protein contents of total p53 and serine-15 phosphorylated p53. The transcript expression of the DNA-repairing enzyme, Rad23A, was significantly suppressed in compressed muscles. Our time-course study indicated that increased oxidative/nitrosative stress and proapoptotic signalling were maintained in muscles receiving increasing amount of compression cycles and post-compression time. Furthermore, resveratrol was found to attenuate the histological damage, oxidative/nitrosative stress and proapoptotic signalling in response to prolonged moderate compression. In conclusion, our findings are consistent with the hypothesis that oxidative stress and DNA damage signalling in skeletal muscle are involved in the underlying mechanisms responsible for the pathogenesis of pressure-induced deep tissue injury.