Lipid hydroperoxides promote sarcopenia through carbonyl stress

Abstract

Reactive 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.

Inhibition of the skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity

“…HU did not affect extensor digitorum longus (EDL) mass but robustly decreased force-generating capacity (Figure S1A,B). As previously described, 5,33 HU led to a robust accumulation of 4-hydroxnonenal (4-HNE) in skeletal muscle (Figure 1F, Ponceau S. staining in Figure S1C).…”

“…28,29 Our group and others have found overexpression of GPx4 can neutralize LOOH and/or lipid carbonyls to rescue muscle atrophy and weakness with aging, disuse, and denervation. 5,30,31 In these studies, GPx4 overexpression was germline, suggesting that these mice were protected from an increase in LOOH in all their cell-types, not just skeletal muscle. 5,30 Similarly, treatment with liproxstatin-1, carnosine, or N-acetylcarnosine is effective to suppress LOOH or lipid carbonyls and prevent disuse-induced muscle atrophy, 4,5 but these compounds would be predicted to reduce lipid carbonyl stress throughout the body.…”

“…Mice underwent 7 days of HU with two mice per cage utilizing the same protocol used previously by our group. 5,33 These mice were checked daily to ensure food and water consumption and to measure body mass. After the 7 days of HU, the mice were fasted for 4 h then received an intraperitoneal injection of 80 mg/kg ketamine and 10 mg/kg xylazine.…”

“…3 Recently, our laboratory and others have identified the role of a lipid-specific form of ROS known as lipid hydroperoxides (LOOH) in disuse-induced skeletal muscle atrophy. [4][5][6][7] LOOH has been previously identified to play a role in the induction of ferroptosis, a non-apoptotic iron-dependent form of regulated cell death. 8 Polyunsaturated fatty acids (PUFAs) provide the essential double bonds in the synthesis of LOOH.…”

MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death

“…Multiple studies have linked decreased AKR and ALDH activity with increased ferroptosis susceptibility, suggesting that successful LDE clearance at least delays ferroptotic cell death (19, 64, 65). While it has long been known that LDE levels are increased during ferroptosis, recent reports showed that sublethal levels of 4-HNE and RSL3 or erastin display synergistic behaviour to induce ferroptotic cell death (65) and position LDEs as mediators of altered metabolism in ferroptotic cells (66, 67). Additionally, treatment with conjugated PUFAs, which can react by peroxyl radical addition mechanisms to more readily form LDEs and truncated PLs compared to non-conjugated PUFAs (22, 68), leads to elevated LDE-mediated damage and induces ferroptotic cell death without the need for exposure to a canonical ferroptosis inducer (69).…”