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

Publication date: Available online 23 March 2019Source: Redox BiologyAuthor(s): 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 ZitoAbstractSelenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to congenital myopathies associated with insulin resistance (SEPN1-related myopathies). 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 susce...
Source: Redox Biology - Category: Biology Source Type: research