Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C059

Oral Communications

The obesity-independent impact of hyperlipidaemia and atherosclerosis on skeletal muscle metabolism and redox biology

P. P. Sfyri1, N. Y. Yuldasheva2, N. Giallourou3, A. Tzimou4, J. R. Swann3, V. Mougios4, M. T. Kearney2, A. Matsakas1

1. Centre for Atherothrombotic & Metabolic Disease, Hull York Medical School, Hull, United Kingdom. 2. Leeds Institute of Genetics Health and Therapeutics, University of Leeds, Leeds, United Kingdom. 3. Department of Surgery and Cancer, Division of Computational and Systems Medicine, Imperial College London, London, United Kingdom. 4. School of Physical Education and Sports Science, Laboratory of Evaluation of Human Biological Performance, Aristotle University of Thessaloniki, Thessaloniki, Greece.


Hyperlipidaemia and atherosclerosis, in the context of obesity, are considered significant risk factors for pathophysiological changes in peripheral tissues, such as the liver and adipose tissue [1,2]. However, both hyperlipidaemia and atherosclerosis can occur in the absence of obesity and their impact on skeletal muscle is not understood sufficiently [3]. In this regard, we used the Apolipoprotein E-deficient (ApoE-/-) mouse model, an established model of obesity-independent hyperlipidaemia and atherosclerosis, to determine the impact of Western-type diet (WD) and ApoE deficiency on skeletal muscle morphological, metabolic and biochemical properties. Data were analysed by two-way ANOVA (genotype x diet). We found that individual myofibres were significantly enlarged due to extensive lipid accumulation and most importantly the ex vivo myogenic potential of skeletal muscle stem cells from ApoE-/- mice was impaired, showing attenuated differentiation. Ectopic lipid accumulation in skeletal muscle was accompanied by a transition towards more oxidative myofibres and enhanced capillarisation, possibly representing a metabolic adaptation in response to atherogenic diet and ApoE deficiency. However, metabonomic analysis and gene expression of skeletal muscle revealed perturbed fatty acid metabolism and impaired mitochondrial metabolism. Moreover, ApoE deficiency and diet independently induced oxidative stress, as shown by elevated lipid peroxidation and oxidative protein and DNA modifications in the skeletal muscle. Most importantly, pharmacological inhibition of NADPH oxidase 2 (Nox2) with the use of the Nox2ds-tat peptide inhibitor decreased superoxide production, DNA damage and protein carbonylation, one of the most harmful protein modifications, in the muscle of ApoE-/- mice. These data indicate that hyperlipidaemia and atherosclerosis alter morphological features, induce oxidative damage and impair mitochondrial metabolism in skeletal muscle independently of obesity that can be mitigated by Nox2 inhibition, highlighting its role as a potential therapeutic target for attenuating oxidative stress in skeletal muscle.

Where applicable, experiments conform with Society ethical requirements