Sepsis-induced muscle proteolysis is blocked by glycogen synthase kinase (GSK)-3 beta inhibitors

Abstract

Abstract Introduction: Muscle wasting in sepsis is mainly caused by increased degradation of proteins, in particular the myofibrillar proteins actin and myosin. Recent studies suggest that inactivation of GSK-3beta, a downstream enzyme in the PI3K signaling pathway, may prevent muscle atrophy. The role of GSK-3beta in sepsis-induced muscle proteolysis is not known. We tested the hypothesis that inhibition of GSK-3beta reduces protein breakdown in septic muscle. Methods: Male Sprague-Dawley rats underwent induction of sepsis by cecal ligation and puncture (CLP) or were sham-operated. After 16 hours, paired extensor digitorum longus (EDL) muscles were incubated for 2 hours under physiological conditions in the absence or presence of one of the GSK-3beta inhibitors, lithium chloride (LiCl, 50 millimolar) or thiadiazolidinone-8 (TDZD-8, 25 micromolar). Protein breakdown rates were determined by measuring the net release of free tyrosine. Results: Sepsis resulted in a substantial increase in muscle protein breakdown, confirming previous observations. Treatment of incubated muscles with either of the GSK-3beta inhibitors significantly reduced protein breakdown in muscle from septic rats. LiCl also reduced basal protein degradation. ∗−LiCl+LiCl−TDZD-8+TDZD-8SHAM266.7 ± 21.7186.6 ± 15.1∗272.9 ± 8.6210.2 ± 15.7CLP475.0 ± 43.1301.7 ± 16.6∗418.6 ± 42.8301.4 ± 31.4∗∗Results are mean ± SEM with n=8 in each group;∗p Conclusions: Inhibition of GSK-3beta may reduce muscle protein breakdown during sepsis and perhaps other muscle-wasting conditions as well.