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

Ersilia Varone, Diego Pozzer, Simona Di Modica, Alexander Chernorudskiy, Leonardo Nogara, Martina Baraldo, Mario Cinquanta, Stefano Fumagalli, Rocio Nur Villar-Quiles, Maria-Grazia De Simoni, Bert Blaauw, Ana Ferreiro, Ester Zito

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)101176
JournalRedox Biology
Volume24
DOIs
Publication statusPublished - Jun 2019

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    Varone, E., Pozzer, D., Di Modica, S., Chernorudskiy, A., Nogara, L., Baraldo, M., Cinquanta, M., Fumagalli, S., Villar-Quiles, R. N., De Simoni, M-G., Blaauw, B., Ferreiro, A., & Zito, E. (2019). SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biology, 24, 101176. https://doi.org/10.1016/j.redox.2019.101176