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Targeted disruption of inducible nitric oxide synthase protects against age-related s-nitrosation and insulin resistance in muscle of male mice

Abstract

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. (AU)

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