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

• DOI: 10.2337/db12-0339
• Publication Date: 2012-09-19T07:41:54Z
• Authors: Eduardo R. Ropelle; José R. Pauli; Dennys E. Cintra; Adelino S. da Silva; Cláudio T. De Souza; Dioze Guadagnini; Bruno M. Carvalho; Andrea M. Caricilli; Carlos K. Katashima; Marco A. Carvalho...; Sandro Hirabara; Rui Curi; Lício A. Velloso; Mario J.A. Saad; José B.C. Carvalh...
• Keywords: Male; 0301 basic medicine; Aging; Insulin/metabolism; Nitrosation; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type II/antagonists & inhibitors; Inbred C57BL; Mice; 03 medical and health sciences; Signal Transduction/drug effects; Physical Conditioning, Animal; Animals; Insulin; Enzyme Inhibitors; Muscle, Skeletal; Skeletal/drug effects; Enzyme Inhibitors/pharmacology; Lysine/analogs & derivatives; Animal; Lysine; Physical Conditioning; Mice, Inbred C57BL; Aging/drug effects; Muscle; Insulin Resistance; Insulin Resistance/physiology; Signal Transduction

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.