title: Targeted disruption of inducible nitric oxide synthase protects against aging, 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.
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences State University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.forename: José R
authors.initials: JR
authors.lastname: Pauli
authors.forename: Dennys E
authors.initials: DE
authors.lastname: Cintra
authors.forename: Adelino S
authors.initials: AS
authors.lastname: da Silva
authors.forename: Cláudio T
authors.initials: CT
authors.lastname: De Souza
authors.forename: Dioze
authors.initials: D
authors.lastname: Guadagnini
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Carvalho
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Caricilli
authors.forename: Carlos K
authors.initials: CK
authors.lastname: Katashima
authors.forename: Marco A
authors.initials: MA
authors.lastname: Carvalho-Filho
authors.forename: Sandro
authors.initials: S
authors.lastname: Hirabara
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
authors.forename: José B C
authors.initials: JB
authors.lastname: Carvalheira
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015538:Nitrosation; D010805:Physical Conditioning, Animal; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine