99 NOX2-driven attenuation of oxidative stress in skeletal muscle of atherosclerotic mice

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Abstract

Background

Obesity leading to hyperlipidaemia and atherosclerosis is recognised to induce morphological and metabolic changes in many tissues including skeletal muscle and the liver. However, both hyperlipidaemia and atherosclerosis can occur in the absence of obesity. The impact of the latter scenario on skeletal muscle and liver is not understood sufficiently. In this regard, we used the Apolipoprotein E-deficient (ApoE-/-) mouse model, an established model of hyperlipidaemia and atherosclerosis, that does not become obese when subjected to a high-fat diet, to determine the impact of western-type diet (WD) and ApoE deficiency on skeletal muscle morphological, metabolic and biochemical properties. To establish the potential of therapeutic targets, we further examined the impact of Nox2 pharmacological inhibition on skeletal muscle redox biology.

Methods

ApoE-/- mice were fed a standard chow or WD for 12 weeks. A subgroup of ApoE-/- mice on WD were treated with Nox2ds-tat using osmotic minipumps. Skeletal muscle and liver specimens were evaluated by histological, biochemical, metabonomics and molecular biology methods. Statistical analysis was performed by two-way ANOVA, Student’s t-tests and chi-square test as appropriate.

Results

Obesity-independent hyperlipidaemia and atherosclerosis induces ectopic lipid accumulation in skeletal muscle and the liver and ApoE deficiency alters skeletal muscle morphology and intramuscular fat contents. Increased fibre size was accompanied by a transition towards slower myofibres and enhanced capillarisation, indicative of a functional remodelling. We found perturbed gene expression for fatty acid uptake and oxidation and altered mitochondrial metabolism as shown by metabonomic analysis, pinpointing a detrimental impact of lipid accumulation on muscle metabolome. Importantly, there was enhanced oxidative stress in the skeletal muscle and development of liver steatosis, inflammation and oxidative stress. Pharmacological inhibition of Nox2 decreased reactive oxygen species (ROS) production and protein oxidative modifications in the muscle of ApoE-/- mice subjected to a western-type diet.

Conclusions

This study provides key evidence to better understand the pathophysiology of skeletal muscle in the context of hyperlipidaemia and atherosclerosis and identifies Nox2 as a potential target for attenuating oxidative stress in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis.

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