Lipid hydroperoxides promote muscle atrophy through lysosomal amplification

Abstract

AbstractReactive oxygen species (ROS) is a cardinal feature of skeletal muscle atrophy. However, ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength.1,2 Here we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by suppression of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. Strikingly, genetic and pharmacologic suppression of muscle LOOH robustly prevented the reduction of both muscle mass and force-generating capacity. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner, and the suppression of autophagic machinery was sufficient to prevent muscle atrophy and weakness. Indeed, the lysosome is essential for the amplification of LOOH induced by oxidative stress. Our findings provide novel insights for the role of LOOH in muscle atrophy including a therapeutic implication by pharmacologic suppression.