INOS Inhibitor, L-NIL, Reverses Burn-induced Glycogen Synthase Kinase-3β Activation in Skeletal Muscle of Rats

Overview

Journal Metabolism

Specialty Endocrinology

Date 2012 Sep 22

PMID 22995863

Citations 6

Authors

Masao Kaneki

Yuji Fukushima

Shohei Shinozaki

Makiko Fukaya

Mayu Habiro

Nobuyuki Shimizu

Kyungho Chang

Shingo Yasuhara

J A Jeevendra Martyn

Affiliations

Soon will be listed here.

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 (160-190g) by immersing the back of the trunk for 15s and the abdomen for 8s in 80°C water. Burned and sham-burned rats were treated with L-NIL (60mg/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.

Citing Articles

Targeting iNOS Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage via Promoting Ferroptosis of M1 Microglia and Reducing Neuroinflammation.

Qu W, Cheng Y, Peng W, Wu Y, Rui T, Luo C Mol Neurobiol. 2022; 59(5):3124-3139.

PMID: 35262869 DOI: 10.1007/s12035-022-02788-5.

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

Sumsuzzman D, Choi J, Khan Z, Hong Y Antioxidants (Basel). 2020; 9(12).

PMID: 33261180 PMC: 7760393. DOI: 10.3390/antiox9121196.

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

Kashiwagi S, Khan M, Yasuhara S, Goto T, Kem W, Tompkins R Shock. 2016; 47(1):61-69.

PMID: 27529131 PMC: 5167674. DOI: 10.1097/SHK.0000000000000729.

Role of protein farnesylation in burn-induced metabolic derangements and insulin resistance in mouse skeletal muscle.

Nakazawa H, Yamada M, Tanaka T, Kramer J, Yu Y, Fischman A PLoS One. 2015; 10(1):e0116633.

PMID: 25594415 PMC: 4296934. DOI: 10.1371/journal.pone.0116633.

Temporal study following burn injury in young rats is associated with skeletal muscle atrophy, inflammation and altered myogenic regulatory factors.

Quintana H, Bortolin J, da Silva N, Pidone Ribeiro F, Liberti E, Ribeiro D Inflamm Res. 2014; 64(1):53-62.

PMID: 25413930 DOI: 10.1007/s00011-014-0783-8.

References

Sugita H, Fujimoto M, Yasukawa T, Shimizu N, Sugita M, Yasuhara S . Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells. J Biol Chem. 2005; 280(14):14203-11. DOI: 10.1074/jbc.M411226200. View

Schweickert W, Hall J . ICU-acquired weakness. Chest. 2007; 131(5):1541-9. DOI: 10.1378/chest.06-2065. View

Thomas J, Schlender K, Larner J . A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968; 25(1):486-99. DOI: 10.1016/0003-2697(68)90127-9. View

Kim J, Kim Y, Fillmore J, Chen Y, Moore I, Lee J . Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001; 108(3):437-46. PMC: 209353. DOI: 10.1172/JCI11559. View

Fang C, Li B, James J, King J, Evenson A, Warden G . Protein breakdown in muscle from burned rats is blocked by insulin-like growth factor i and glycogen synthase kinase-3beta inhibitors. Endocrinology. 2005; 146(7):3141-9. DOI: 10.1210/en.2004-0869. View

Song K, Scherer P, Tang Z, Okamoto T, Li S, Chafel M . Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J Biol Chem. 1996; 271(25):15160-5. DOI: 10.1074/jbc.271.25.15160. View

Rommel C, Bodine S, Clarke B, Rossman R, Nunez L, Stitt T . Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol. 2001; 3(11):1009-13. DOI: 10.1038/ncb1101-1009. View

Carvalho-Filho M, Ueno M, Carvalheira J, Velloso L, Saad M . Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice. Am J Physiol Endocrinol Metab. 2006; 291(3):E476-82. DOI: 10.1152/ajpendo.00422.2005. View

Sugita H, Kaneki M, Sugita M, Yasukawa T, Yasuhara S, Martyn J . Burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle. Am J Physiol Endocrinol Metab. 2004; 288(3):E585-91. DOI: 10.1152/ajpendo.00321.2004. View

10.

Friedrich O . Critical illness myopathy: what is happening?. Curr Opin Clin Nutr Metab Care. 2006; 9(4):403-9. DOI: 10.1097/01.mco.0000232900.59168.a0. View

11.

Shinozaki S, Choi C, Shimizu N, Yamada M, Kim M, Zhang T . Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice. J Biol Chem. 2011; 286(40):34959-75. PMC: 3186386. DOI: 10.1074/jbc.M110.187666. View

12.

Summers S, Kao A, Kohn A, Backus G, Roth R, Pessin J . The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. J Biol Chem. 1999; 274(25):17934-40. DOI: 10.1074/jbc.274.25.17934. View

13.

Martyn J, Kaneki M, Yasuhara S . Obesity-induced insulin resistance and hyperglycemia: etiologic factors and molecular mechanisms. Anesthesiology. 2008; 109(1):137-48. PMC: 3896971. DOI: 10.1097/ALN.0b013e3181799d45. View

14.

Sugita M, Sugita H, Kim M, Mao J, Yasuda Y, Habiro M . Inducible nitric oxide synthase deficiency ameliorates skeletal muscle insulin resistance but does not alter unexpected lower blood glucose levels after burn injury in C57BL/6 mice. Metabolism. 2011; 61(1):127-36. PMC: 3304504. DOI: 10.1016/j.metabol.2011.06.001. View

15.

Cha H, Song S, Kim Y, Kim J, Won K, Park S . Lack of inducible nitric oxide synthase prevents lipid-induced skeletal muscle insulin resistance without attenuating cytokine level. J Pharmacol Sci. 2011; 117(2):77-86. DOI: 10.1254/jphs.11093fp. View

16.

Yu Y, Tompkins R, Ryan C, Young V . The metabolic basis of the increase of the increase in energy expenditure in severely burned patients. JPEN J Parenter Enteral Nutr. 1999; 23(3):160-8. DOI: 10.1177/0148607199023003160. View

17.

Rylatt D, Aitken A, Bilham T, Condon G, Embi N, Cohen P . Glycogen synthase from rabbit skeletal muscle. Amino acid sequence at the sites phosphorylated by glycogen synthase kinase-3, and extension of the N-terminal sequence containing the site phosphorylated by phosphorylase kinase. Eur J Biochem. 1980; 107(2):529-37. View

18.

Fang C, Li B, James J, Yahya A, Kadeer N, Guo X . GSK-3beta activity is increased in skeletal muscle after burn injury in rats. Am J Physiol Regul Integr Comp Physiol. 2007; 293(4):R1545-51. DOI: 10.1152/ajpregu.00244.2007. View

19.

MacAulay K, Blair A, Hajduch E, Terashima T, Baba O, Sutherland C . Constitutive activation of GSK3 down-regulates glycogen synthase abundance and glycogen deposition in rat skeletal muscle cells. J Biol Chem. 2005; 280(10):9509-18. DOI: 10.1074/jbc.M411648200. View

20.

Perreault M, Marette A . Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med. 2001; 7(10):1138-43. DOI: 10.1038/nm1001-1138. View