Submitted on April 11, 2007
Accepted on August 3, 2007
GSK-3
ACTIVITY IS INCREASED IN SKELETAL MUSCLE AFTER BURN INJURY IN RATS
Cheng-Hui Fang1*, Bingguo Li1, J. Howard James2, Ayesha Yahya3, Nijiati Kadeer4, Xialing Guo4, Chun Xiao5, Dorothy M. Supp6, Richard J Kagan7, Per-Olof Hasselgren8, and Sulaiman Sheriff5
1 Shriners Hospitals for Children-Cincinnati Burns Hospital, Cincinnati, Ohio, United States
2 Surgery, University of Cincinnati, Cincinnati, Ohio, United States; Shriners Hospitals for Children-Cincinnati Burns Hospital, Cincinnati, Ohio, United States
3 Surgery, University of Cincinnati, California, United States
4 Cincinnati, Ohio, United States; Shriners Hospitals for Children-Cincinnati Burns Hospital, Cincinnati, Ohio, United States
5 Cincinnati, Ohio, United States; Surgery, University of Cincinnati, California, United States
6 Shriners Hospitals for Children, Cincinnati Burns Hospital, Cincinnati, Ohio, United States
7 Cincinnati, Ohio, United States; Shriners Hospitals for Children, Cincinnati Burns Hospital, Cincinnati, Ohio, United States
8 Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: c-hfang{at}hotmail.com.
Previous reports suggest that burn-induced muscle proteolysis can be inhibited by treatment with GSK-3
inhibitors, suggesting that burn injury may be associated with increased GSK-3b activity. The influence of burn injury on muscle GSK-3 kinase activity, however, is not known. We determined the effect of a 30% total body surface full-thickness burn injury in rats on muscle GSK-3 activity by measuring GSK-3 kinase activity and tissue levels of serine 9 phosphorylated GSK-3, p(Ser9)-GSK-3, by Western blotting and immunohistochemistry. Because burn-induced muscle wasting is, at least in part, mediated by glucocorticoids, we used dexamethasone-treated cultured muscle cells in which GSK-3 expression had been reduced with siRNA to further assess the role of GSK-3b in muscle atrophy. Burn injury resulted in a 7-fold increase in GSK-3 kinase activity in skeletal muscle. This effect of burn was accompanied by reduced tissue levels of p(Ser9)-GSK-3, suggesting that burn injury stimulates GSK-3 in skeletal muscle secondary to inhibited phosphorylation of the enzyme. In addition, burn injury resulted in inhibited phosphorylation and activation of Akt, an upstream regulatory mechanism of GSK-3 activity. Reducing the expression of GSK-3 in cultured muscle cells with siRNA inhibited dexamethasone-induced protein degradation by approximately 50%. The results suggest that burn injury stimulates GSK-3 activity in skeletal muscle and that GSK-3 may, at least in part, regulate glucocorticoid-mediated muscle wasting.
