iNOS inhibitor, L-NIL, reverses burn-induced glycogen synthase kinase-3β activation in skeletal muscle of rats

Abstract

Objectives Recent studies suggest that activation of glycogen synthase kinase (GSK)-3β may be involved in burn injury-induced metabolic derangements and protein breakdown in skeletal muscle. However, the mechanism for GSK-3β activation after burn injury is unknown. To investigate the role of inducible nitric oxide synthase (iNOS) in this scenario, a major mediator of inflammation, we examined the effects of a specific inhibitor for iNOS, L-NIL, on GSK-3β activity in skeletal muscle of burned rats. Materials/Methods Full-thickness third degree burn injury comprising 40% of total body surface area was produced under anesthesia in male Sprague-Dawley rats (160–190 g) by immersing the back of the trunk for 15 sec and the abdomen for 8 sec in 80°C water. Burned and sham-burned rats were treated with L-NIL (60 mg/kg BW, b.i.d., IP) or phosphate-buffered saline for three days. GSK-3β activity in skeletal muscle was evaluated by immune complex kinase assay, and by phosphorylation status of GSK-3β and its endogenous substrate, glycogen synthase. Results GSK-3β activity was increased in a time-dependent manner in skeletal muscle after burn injury, concomitant with the induction of iNOS expression. iNOS inhibitor, L-NIL, reverted the elevated GSK-3β activity in skeletal muscle of burned rats, although L-NIL did not alter GSK-3β activity in sham-burned rats. Conclusions Our results clearly indicate that iNOS plays an important role in burn injury-induced GSK-3β activation in skeletal muscle. These findings suggest that iNOS may contribute to burn injury-induced metabolic derangements, in part, by activating GSK-3β.

Role of Protein Farnesylation in Burn-Induced Metabolic Derangements and Insulin Resistance in Mouse Skeletal Muscle

“…Next, we examined the effects of FTI-277 on burn-induced metabolic alterations. Consistent with previous studies [ 41 ], glycogen content in skeletal muscle of vehicle-treated burned mice was markedly decreased to 22% of that of vehicle-treated sham-burned mice (p<0.05). FTI-277 treatment restored glycogen content in burned mice to the level comparable to those in sham-burned mice ( Fig.…”

“…Consistent with our previous studies in rodents [ 31 , 32 , 41 , 47 ], burn injury resulted in: (1) attenuated insulin-stimulated phosphorylation of IR, IRS-1, Akt and GSK-3β (Figs. 2 , 3 ); (2) decreased IRS-1 protein expression ( Fig.…”

Prevention of Burn-Induced Inflammatory Responses and Muscle Wasting by GTS-21, a Specific Agonist for α7 Nicotinic Acetylcholine Receptors

“…In a second set of experiment, molecular signals of inflammatory and proteolytic pathways were examined at post burn day1 (PBD1). Our previous work documented that proteolytic and inflammatory signals begin to change significantly at day1 and peak at day 2 after burn (31). Meanwhile, our preliminary study also indicated that atrogenes expression were significantly elevated at PBD1 and returned to basal levels at post burn day 3 (PBD3, Supplemental Figure 1).…”

Protective Effects of Melatonin against Severe Burn-Induced Distant Organ Injury: A Systematic Review and Meta-Analysis of Experimental Studies

“…Nitrotyrosine, a biomarker of inflammation [90][91][92], can increase with iNOS expression in full-thickness third-degree burn injury (40% TBSA burn) [93]. On the other hand, the nitrotyrosine contents are markedly reduced by the iNOS inhibitor [93]. Interestingly, we found one study that shows nitrotyrosine levels was peak in ileum tissue of post-burn rats, whereas this marker was apparent significantly decreased in MT treated rats [78].…”

“…However, recent evidence suggests that intestinal inflammation may contribute to intestinal barrier disruption [88,89]. Nitrotyrosine, a biomarker of inflammation [90][91][92], can increase with iNOS expression in full-thickness third-degree burn injury (40% TBSA burn) [93]. On the other hand, the nitrotyrosine contents are markedly reduced by the iNOS inhibitor [93].…”