Targeted Disruption of Inducible Nitric Oxide Synthase Protects Against Aging, S-Nitrosation, and Insulin Resistance in Muscle of Male Mice
- Eduardo R. Ropelle1,2,
- José R. Pauli2,
- Dennys E. Cintra2,
- Adelino S. da Silva3,
- Cláudio T. De Souza4,
- Dioze Guadagnini1,
- Bruno M. Carvalho1,
- Andrea M. Caricilli1,
- Carlos K. Katashima1,
- Marco A. Carvalho-Filho1,
- Sandro Hirabara5,
- Rui Curi5,
- Lício A. Velloso1,
- Mario J.A. Saad1 and
- José B.C. Carvalheira1⇓
- 1Department of Internal Medicine, Faculty of Medical Sciences State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- 2School of Applied Sciences, UNICAMP, Limeira, São Paulo, Brazil
- 3School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paolo, Brazil
- 4Laboratory of Exercise Biochemistry and Physiology, Health Science Unit, University of Southern Santa Catarina (UNESC) Criciúma, Santa Catarina, Brazil
- 5Department of Physiology and Biophysics, University of São Paulo, São Paulo, São Paulo, Brazil
- Corresponding author: José B.C. Carvalheira, .
E.R.R. and J.R.P. contributed equally to this work.
Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation–induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway.
- Received March 27, 2012.
- Accepted July 25, 2012.
- © 2013 by the American Diabetes Association.
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