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Rôle du stress oxydant dans les altérations mitochondriales et/ou le développement de l'insulino-résistance dans le muscle squelettique. – MITOCHROS

Submission summary

Insulin resistance (IR) is a key defect associated with obesity and type 2 diabetes (T2D). The precise factors that lead to IR have not been elucidated fully, but there is a strong association between IR and inappropriate lipid accumulation in insulin-target tissues. Over the past decade, several studies have reported changes in markers of mitochondrial metabolism in insulin-resistant individuals, leading to the theory that altered mitochondrial oxidative function, particularly in skeletal muscle, could cause lipid accumulation and the development of IR. However, whether mitochondrial dysfunction was a primary cause or a consequence of IR was unclear until now. Our recent work suggests that mitochondrial alterations are a not a cause of IR but rather a consequence of increased oxidative stress in skeletal muscle of diet-induced insulin-resistant mice. Nevertheless, by promoting lipid accumulation, mitochondrial alterations could participate to the maintenance or to the exacerbation of impaired insulin sensitivity. In addition, oxidative stress, which precedes mitochondrial alterations in the course of diet-induced IR, could also play a role in the development of IR. Consequently, it is fundamental 1) to investigate the molecular mechanisms by which increased reactive oxygen species (ROS) production in skeletal muscle could alter mitochondria structure and function, in order to propose strategies to stimulate lipid oxidation and decrease lipotoxicity, and 2) to determine whether increased oxidative stress could participate itself to the development of IR, in parallel to the effects on mitochondria. For that, we will firstly analyze the protective role of antioxidant treatments on the development mitochondrial dysfunction in diet-induced diabetic mice. We will use different antioxidants and inhibitors of ROS production in order to identify the intracellular sources of ROS production in skeletal muscle of diabetic mice. Secondly, we will investigate the molecular mechanisms of ROS-induced mitochondrial alterations. Based on preliminary data, we will investigate 3 hypothesis: i) a reduction of mitochondrial DNA (mtDNA) replication, ii) an increase of acetylated mitochondrial proteins associated with reduced sirtuin expression/activity, iii) an increase of mitochondrial protein oxidation, leading to a reduction of their quantity and/or activity. Lastly, we will investigate, both in vivo and in vitro, the causative role of ROS in the development of IR. Particularly, we will focus on the identification of (new) ROS-activated serine/threonine kinases and/or their substrates, mediating IR in skeletal muscle. Consequently, a better understanding of the molecular mechanisms by which ROS induce mitochondrial damages and/or alter insulin signalling could allow defining new preventive and therapeutic strategies to limit their production and/or to counteract their damaging affects, leading to an improvement of oxidative capacities of skeletal muscle and of insulin sensitivity.

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