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.

Excessive training impairs the insulin signal transduction in mice skeletal muscles

“…The beneficial effects of acute and chronic moderate intensity exercise on the glucose metabolism in skeletal muscle cells of aging, obese, and sedentary rodents may be mediated by key proteins of the insulin-dependent signaling pathway (Luciano et al 2002, Ropelle et al 2006, 2013, Pauli et al 2008. The binding of insulin to its receptor activates the insulin receptor (IR) tyrosine kinase, while phosphorylating intracellular protein substrates such as the insulin receptor substrate 1 (IRS1).…”

“…Indeed, some inflammatory signaling proteins such as the IκB kinase (IKK), the nuclear factor kappa B (NFκB), the stressactivated protein kinases/Jun amino-terminal kinases (SAPK/JNK), and the tumor necrosis factor alpha (TNFα) play a fundamental role in the phosphorylation (p) of IRS1 at serine 307, impairing the insulin signal transduction (Kahn et al 2006, Vichaiwong et al 2009, Prasannarong et al 2012, Ropelle et al 2013. In contrast to the aforementioned beneficial effects of exercise (Luciano et al 2002, Ropelle et al 2006, 2013, Pauli et al 2008, our research group verified that an overtraining (OT) protocol based on downhill running sessions decreased the pIRβ (Tyr1146) and pAkt (Ser473) with concomitant upregulation of the pIKKα/β (Ser176/180), pSAPK/JNK (Thr183/Tyr185), and pIRS1 (Ser307) in skeletal muscles with different fiber type specificities (Pereira et al 2014a).…”

Molecular mechanisms of glucose uptake in skeletal muscle at rest and in response to exercise

“…Specifically, aberrant production of NO in mammals appears to be mediated by the inducible isoform, iNOS, which is highly expressed in certain situations such as oxidative stress and inflammation. In light of these findings, it was demonstrated that iNOS knockout mice are protected from developing insulin resistance induced by obesity 57 and aging 58 . Interestingly, it was observed that acute aerobic exercise can reduce the protein content of iNOS, S-nitrosation of IRβ, IRS-1 and Akt and, thus, decrease insulin resistance in the skeletal muscle of obese rats 59 .…”

Compostos bioativos com potencial ação no controle da homeostase glicêmica

“…Compreender as causas e os fatores determinantes de seu incremento epidêmico torna-se imprescindível na busca de soluções para retardar ou reverter a progressão desta alarmante realidade epidemiológica (ROPELLE et al, 2013). Segundo a Sociedade Brasileira de Diabetes, 33% da população brasileira dos 60 aos 79 anos de idade têm diabetes ou alguma alteração relacionada à glicose (OMS, 2011;BRASIL, 2011).…”

“…Nesse sentido, diversos estudos são realizados visando identificar novas moléculas com ações regulatórias sobre a via de sinalização da insulina e consequentemente na homeostase da glicose (ROPELLE et al, 2013;MOURA, 2015). se apresentar ciclizado (anel C) apresentando estrutura geral C6-C3-C6.…”