SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance - Unité de Biologie Fonctionnelle et Adaptative Accéder directement au contenu
Article Dans Une Revue Redox Biology Année : 2019

SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance

Résumé

Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to a congenital myopathy associated with insulin resistance (SEPN1-related myopathy). The exact cause of the insulin resistance in patients with SELENON loss of function is not known. Skeletal muscle is the main contributor to insulin-mediated glucose uptake, and a defect in this muscle-related mechanism triggers insulin resistance and glucose intolerance. We have studied the chain of events that connect the loss of SELENON with defects in insulin-mediated glucose uptake in muscle cells and the effects of this on muscle performance. Here, we show that saturated fatty acids are more lipotoxic in SELENON-devoid cells, and blunt the insulin-mediated glucose uptake of SELENON-devoid myotubes by increasing ER stress and mounting a maladaptive ER stress response. Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat diet mirrors the features of saturated fatty acid-treated myotubes, and show signs of myopathy with a compromised force production. These findings suggest that the absence of SELENON together with a high-fat dietary regimen increases susceptibility to insulin resistance by triggering a chronic ER stress in skeletal muscle and muscle weakness. Importantly, our findings suggest that environmental cues eliciting ER stress in skeletal muscle (such as a high-fat diet) affect the pathological phenotype of SEPN1-related myopathy and can therefore contribute to the assessment of prognosis beyond simple genotype-phenotype correlations.
Fichier principal
Vignette du fichier
1-s2.0-S2213231719301788-main.pdf (4.47 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

hal-02165757 , version 1 (26-06-2019)

Identifiants

Citer

Ersilia Varone, Diego Pozzer, Simona Di Modica, Alexander Chernorudskiy, Leonardo Nogara, et al.. SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biology, 2019, 24, pp.101176. ⟨10.1016/j.redox.2019.101176⟩. ⟨hal-02165757⟩
30 Consultations
23 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More