iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53

Abstract

Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn)-induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-κB and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-κB and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S-nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-κB and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn-induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S-nitrosylation and acetylation and DNA-binding capacity of p65 NF-κB and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylation-dependent activation (acetylation) of p65 NF-κB. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury.

A systematic review of p53 regulation of oxidative stress in skeletal muscle

“…The most common manipulations of muscle include crush injury, tissue autografting, disease, and burn injury which can lead to direct skeletal muscle atrophy, or indirect atrophy through immobilization [67][68][69][70][71][72]. Tissue crush injury, involving a significant disruption to muscle structure but preserving blood and nerve supply, leads to impaired myotube…”

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

“…To identify the TNF-α/ IL-6 producing cells, we stained the burn-associated systemic inflammation (23), and to evaluate whether a nonspecific phosphodiesterase inhibitor could attenuate burn-induced inflammatory signaling via the mitogen-activated protein kinase pathway (24). Recently, C57BL/6 mice have also been adopted to investigate inflammatory gene expression induced by burn injury (25).…”

Coenzyme Q10 protects against burn‐induced mitochondrial dysfunction and impaired insulin signaling in mouse skeletal muscle

“…We have previously shown that burn induces mitochondrial dysfunction and insulin resistance in skeletal muscle of mice . We hypothesized that reduced form of CoQ10 (ubiquinol) has protective effects against burn injury‐induced mitochondrial dysfunction and insulin resistance in mouse skeletal muscle.…”