Musclin Inhibits Insulin Activation of Akt/Protein Kinase B in Rat Skeletal Muscle

Abstract

Musclin is a muscle-derived secretory peptide that induces insulin resistance in vitro We studied the effect of musclin (0.5 μg/ml) on insulin-stimulated glucose uptake in rat skeletal muscles and also the effect of rosiglitazone (0.4 μg/ml). Pre-incubation of muscles with musclin resulted in decreased insulin-stimulated glucose uptake. Musclin also reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) mRNAs, although expression of glucose transporter 4 mRNA was unaltered. Rosiglitazone attenuated the effects of musclin on glucose uptake and PPARγ and LXRα mRNA expression. Western blotting demonstrated that activation of protein kinase B (Akt/PKB) in the insulin-signalling cascade was decreased by musclin but corrected by rosiglitazone. These findings suggest that musclin-induced impairment of insulin-stimulated glucose uptake in skeletal muscle is related to Akt/PKB inhibition and might be modulated by PPARγ/LXRα.

Keywords

Rosiglitazone Thiazolidinedione Diabetes Mellitus Rats Musclin Insulin Resistance PPARγ LXRα PI3K Akt/PKB

References

Nieto-Vazquez

Fernández-Veledo

de Alvaro

: Protein-tyrosine phosphatase 1B-deficient myocytes show increased insulin sensitivity and protection against tumor necrosis factor-α-induced insulin resistance. Diabetes 2007; 56: 404–413.

Fernández

Kim

Yakar

: Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev 2001; 15: 1926–1934.

Zisman

Peroni

Abel

: Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 2000; 8: 924–928.

Nishizawa

Matsuda

Yamada

: Musclin, a novel skeletal muscle-derived secretory factor. J Biol Chem 2005; 279: 19391–19395.

Liu

Zong

Liu

: Musclin reduced insulin-induced differented rat myocytes glucose uptake is related to PI3K/AKT (PKB) pathway. Chin J New Drugs 2007; 19: 1585–1588.

Ryder

Yang

Galuska

: Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49: 647–654.

Koistinen

Galuska

Chibalin

: 5-Amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes 2003; 52: 1066–1072.

Lizcano

Alessi

: The insulin signalling pathway. Curr Biol 2002; 12: R236–R238.

Wong

Kim

Peacock

: Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity. Diabetologia 2007; 50: 395–403.

10.

Kurowski

Lin

Lou

: Hyperglycemia inhibits insulin activation of AKT/protein kinase B but not phosphatidylinositol 3-kinase in rat skeletal muscle. Diabetes 1999; 48: 658–663.

11.

Lebovitz

: Type 2 diabetes: An overview. Clin Chem 1999; 45: 1339–1345.

12.

Bhatia

Viswanathan

: Insulin resistance and PPAR insulin sensitizers. Curr Opin Investig Drugs 2006; 10: 891–897.

13.

Chen

Brar

Choi

: Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle. Proc Natl Acad Sci USA 2006; 103: 16580–16585.

14.

Butler

McKay

Popoff

: Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 2002; 51: 1028–1034.

15.

Farese

Sajan

Standaert

: Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): Actions and defects in obesity and type II diabetes. Exp Biol Med 2005; 230: 593–605.

16.

Staiger

Haas

Machicao

: The PPAR agonist troglitazone induces musclin mRNA expression in human myotubes. Horm Metab Res 2006; 38: 614–616.

17.

Gelman

Feige

Desvergne

: Molecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes. Biochim Biophys Acta 2007; 1771: 1094–1107.

18.

Juvet

Andresen

Schuster

: On the role of liver X receptors in lipid accumulation in adipocytes. Mol Endocrinol 2003; 17: 172–182.

19.

Dalen

Ulven

Bamberg

: Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α. J Biol Chem 2003; 278: 48283–48291.