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J. Biol. Chem., Vol. 280, Issue 14, 14203-14211, April 8, 2005

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Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells^*

Hiroki Sugita, Masaki Fujimoto, Takashi Yasukawa, Nobuyuki Shimizu, Michiko Sugita, Shingo Yasuhara, J. A. Jeevendra Martyn, and Masao Kaneki

From the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Shriners Hospital for Children, Harvard Medical School, Boston, Massachusetts 02129

Chronic inflammation plays an important role in insulin resistance. Inducible nitric-oxide synthase (iNOS), a mediator of inflammation, has been implicated in many human diseases including insulin resistance. However, the molecular mechanisms by which iNOS mediates insulin resistance remain largely unknown. Here we demonstrate that exposure to NO donor or iNOS transfection reduced insulin receptor substrate (IRS)-1 protein expression without altering the mRNA level in cultured skeletal muscle cells. NO donor increased IRS-1 ubiquitination, and proteasome inhibitors blocked NO donor-induced reduction in IRS-1 expression in cultured skeletal muscle cells. The effect of NO donor on IRS-1 expression was cGMP-independent and accentuated by concomitant oxidative stress, suggesting an involvement of nitrosative stress. Inhibitors for phosphatidylinositol-3 kinase, mammalian target of rapamycin, and c-Jun amino-terminal kinase failed to block NO donor-induced IRS-1 reduction, whereas these inhibitors prevented insulin-stimulated IRS-1 decrease. Moreover iNOS expression was increased in skeletal muscle of diabetic (ob/ob) mice compared with lean wild-type mice. iNOS gene disruption or treatment with iNOS inhibitor ameliorated depressed IRS-1 expression in skeletal muscle of diabetic (ob/ob) mice. These findings indicate that iNOS reduces IRS-1 expression in skeletal muscle via proteasome-mediated degradation and thereby may contribute to obesity-related insulin resistance.

Received for publication, September 30, 2004 , and in revised form, January 4, 2005.

^* This work was supported by National Institutes of Health Grants R01DK058127 (to M. K.) and R01GM031569, R01GM055082, R01GM061411, and GM21700-Project IV (to J. A. J. M.) and grants from the Shriners Hospital for Children (to J. A. J. M. and S. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1, 2, 3.

To whom correspondence should be addressed: Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth St., Rm. 6604, Charlestown, MA 02129. Tel.: 617-726-8122; Fax: 617-726-8134; E-mail: mkaneki{at}partners.org.

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