Targeted Disruption of Inducible Nitric Oxide Synthase Protects Against Aging, S-Nitrosation, and Insulin Resistance in Muscle of Male Mice

  1. José B.C. Carvalheira1
  1. 1Department of Internal Medicine, Faculty of Medical Sciences State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
  2. 2School of Applied Sciences, UNICAMP, Limeira, São Paulo, Brazil
  3. 3School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paolo, Brazil
  4. 4Laboratory of Exercise Biochemistry and Physiology, Health Science Unit, University of Southern Santa Catarina (UNESC) Criciúma, Santa Catarina, Brazil
  5. 5Department of Physiology and Biophysics, University of São Paulo, São Paulo, São Paulo, Brazil
  1. Corresponding author: José B.C. Carvalheira, carvalheirajbc{at}
  1. 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.

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