Redox Cascade in Chicken Skeletal Muscle: SELENOT Suppression in Selenium Deficiency Triggers Disulfidptosis via mtROS-NADPH Dysregulation.

Abstract

Skeletal muscle atrophy in poultry is characterized by reduced muscle mass and fiber quantity, leading to substantial economic losses in poultry production worldwide. Selenium is an essential trace element that maintains muscle integrity; however, the mechanisms linking Se deficiency to muscle injury remain unclear. Selenoprotein T (SELENOT) is a key regulator of cellular redox homeostasis that has not been fully characterized in skeletal muscles. Se deficiency downregulates SELENOT expression, increases oxidative stress, and induces skeletal muscle atrophy via disulfidase pathways. SELENOT deficiency impaired mitochondrial respiratory chain function, causing mitochondrial reactive oxygen species (mtROS) overproduction, glucose metabolism reprogramming, and Nicotinamide Adenine Dinucleotide Phosphate (NADPH) metabolism disruption. These changes result in cysteine accumulation and disulfidptosis, which lead to abnormal actin disulfide bonding. TEMPO-mediated mtROS inhibition or NADPH supplementation partially rescues Se-deficiency-induced muscle atrophy. SELENOT overexpression alleviates the redox imbalance, NADPH dysfunction, disulfidptosis, and myotube atrophy in Se-deficient cells, whereas rotenone-induced mtROS activation or BAY-876-mediated NADPH inhibition reverses these protective effects. The SELENOT/mtROS/NADPH axis is crucial for Se-deficiency-induced muscle atrophy. This study provides mechanistic insights into muscle-wasting disorders and potential therapeutic targets.