Reactive oxygen species enhance mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle of senescence accelerated prone mice SAMP8

Valentin Barquissau,Frédéric Capel,Dominique Dardevet,Christine Feillet-Coudray,Anne Gallinier,Marie-Agnès Chauvin,Jennifer Rieusset,Béatrice Morio

doi:10.1016/j.freeradbiomed.2017.10.012

Abstract

Whereas reactive oxygen species (ROS) can have opposite impacts on insulin signaling, they have mainly been associated with mitochondrial dysfunction in skeletal muscle. We analyzed the relationship between these three features in skeletal muscle of senescence accelerated mice (SAM) prone (P8), which are characterized by enhanced oxidative stress compared to SAM resistant (R1). Oxidative stress, ROS production, antioxidant system, mitochondrial content and functioning, as well as in vitro and in vivo insulin signaling were investigated in gastrocnemius and quadriceps muscles. In SAMP8 compared to SAMR1, muscle content in carbonylated proteins was two-fold (p < 0.01) and ROS production by xanthine oxidase 70% (p < 0.05) higher. Furthermore, insulin-induced Akt phosphorylation measured in vivo and ex vivo as well as muscle glucose uptake measured ex vivo were significantly higher (p < 0.05). Mitochondrial respiration evidenced uncoupling and higher respiration rates with substrates of complexes II and IV, in agreement with higher maximal activity of complexes II and IV (+ 18% and 62%, respectively, p < 0.05). By contrast, maximal activity of complex I was 22% lower (p < 0.05). All strain differences were corrected after 6 months of N-acetylcysteine (NAC) treatment, thus supporting the involvement of high ROS production in these differences. In conclusion in muscle of SAMP8 compared to SAMR1, high ROS production is associated to higher insulin sensitivity and glucose uptake but to lower mitochondrial complex I activity. These conflicting adaptations, with regards to the resulting imbalance between NADH production and use, were associated with intrinsic adjustments in the mitochondrial respiration chain (mitochondrial uncoupling, enhanced complexes II and IV activity). We propose that these bioenergetics adaptations may help at preserving muscle metabolic flexibility of SAMP8.

Highlights

Skeletal muscle is the main tissue involved in insulin-stimulated glucose disposal, so that insulin resistance in obese and type 2 diabetic patients is mostly accounted for by a default in muscle glucose uptake [1,2]
Oxidative stress in skeletal muscle of senescence-accelerated mice prone 8 (SAMP8) is associated to enhanced xanthine oxidase activity compared to senescence-accelerated mice resistant 1 (SAMR1) We investigated whether reactive oxygen species (ROS) production was increased in muscle of SAMP8 mice, and aimed at identifying the main source which could be related to the higher oxidative stress
Xanthine oxidase is an alternate form of the same gene product of xanthine dehydrogenase, which is the precursor

Summary

Introduction

Skeletal muscle is the main tissue involved in insulin-stimulated glucose disposal, so that insulin resistance in obese and type 2 diabetic patients is mostly accounted for by a default in muscle glucose uptake [1,2]. H2O2 activates signaling pathways involving JNK (c-Jun N-terminal kinase), IKK (nuclear factorkappa B) and NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) that interfere with the insulin signal transduction pathway [6,7,8,9] In those pathological contexts, antioxidant treatments improve or restore insulin sensitivity in various models from cell cultures to humans [10,11,12]. Oxidative stress has been identified as a major cause of mitochondrial damages in skeletal muscle of insulin resistant animals [3] These observations have been performed in diseased models when type 2 diabetes is established. Whereas oxidative stress is a consistent observation in the skeletal muscle of SAMP8 mice, discrepant results have been obtained on the insulin response [20,21,22] and few studies have explored the mitochondrial functions [23,24]

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