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Am J Physiol Regul Integr Comp Physiol 293: R1545-R1551, 2007. First published August 8, 2007; doi:10.1152/ajpregu.00244.2007
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INFLAMMATION AND CYTOKINES

GSK-3beta activity is increased in skeletal muscle after burn injury in rats

Cheng-Hui Fang,1 Bingguo Li,1 J. Howard James,1,2 Ayesha Yahya,2 Nijiati Kadeer,1 Xialing Guo,1 Chun Xiao,2 Dorothy M. Supp,1,2 Richard J. Kagan,1,2 Per-Olof Hasselgren,3 and Sulaiman Sheriff2

1Shriners Hospitals for Children, Cincinnati, Ohio; 2Department of Surgery, University of Cincinnati, Cincinnati, Ohio; and 3Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Submitted 11 April 2007 ; accepted in final form 13 August 2007

Previous reports suggest that burn-induced muscle proteolysis can be inhibited by treatment with GSK-3beta inhibitors, suggesting that burn injury may be associated with increased GSK-3beta activity. The influence of burn injury on muscle GSK-3beta activity, however, is not known. We determined the effect of a 30% total body surface full-thickness burn injury in rats on muscle GSK-3beta activity by measuring GSK-3beta activity and tissue levels of serine 9 phosphorylated GSK-3beta, p(Ser9)-GSK-3beta, by Western blot analysis 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-3beta expression was reduced with small interfering RNA (siRNA) to further assess the role of GSK-3beta in muscle atrophy. Burn injury resulted in a seven-fold increase in GSK-3beta activity in skeletal muscle. This effect of burn was accompanied by reduced tissue levels of p(Ser9)-GSK-3beta, suggesting that burn injury stimulates GSK-3beta 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-3beta activity. Reducing the expression of GSK-3beta in cultured muscle cells with siRNA inhibited dexamethasone-induced protein degradation by ~50%. The results suggest that burn injury stimulates GSK-3beta activity in skeletal muscle and that GSK-3beta may, at least in part, regulate glucocorticoid-mediated muscle wasting.

burn; protein degradation; muscle wasting; Akt activity; atrogin-1; MURF1


Address for reprint requests and other correspondence: C.-H. Fang, Shriners Hospitals for Children, 3229 Burnet Ave., Cincinnati, OH 45229 (e-mail: c-hfang{at}hotmail.com)






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