{Reference Type}: Journal Article
{Title}: SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance.
{Author}: Varone E;Pozzer D;Di Modica S;Chernorudskiy A;Nogara L;Baraldo M;Cinquanta M;Fumagalli S;Villar-Quiles RN;De Simoni MG;Blaauw B;Ferreiro A;Zito E;
{Journal}: Redox Biol
{Volume}: 24
{Issue}: 0
{Year}: 06 2019
{Factor}: 10.787
{DOI}: 10.1016/j.redox.2019.101176
{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.