Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy

Abstract

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg−1 min−1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.

The Emerging Roles of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 in Skeletal Muscle Redox Signaling and Metabolism

“…In experiments infusing Ang-II via osmotic minipumps for 7 days, an NOX2-dependent increase in ROS levels and muscle atrophy was observed in p47phox KO mice (319), demonstrating the necessity of NOX2 activity in the atrophic process induced by AT II (319). This is consistent with another recent study in NOX2 KO mice where the KO mice compared with WT were strongly protected against 4 weeks of AT II infusion-induced skeletal muscle atrophy and associated changes in anabolic and catabolic signaling (169).…”

“…This hormone has been implicated in the pathology of conditions such as cardiac failure and kidney disease-related muscle atrophy (18). The relationship between AT II and NOX2 in skeletal muscle has been evaluated by different researchers (69,169). One study suggested using pharmacological inhibitors that AT II signals via NOX2 to increase intracellular Ca 2+ in mouse EDL skeletal muscle fibers (69).…”

Altered oxidative stress and antioxidant defence in skeletal muscle during the first year following spinal cord injury

“…Several enzymes outside the mitochondria have been implicated in the excessive ROS production in skeletal muscle undergoing atrophy (Kondo et al, ; Derbre et al, ; Kadoguchi et al, ). We detected an increase in XO and NOX2 protein content at 1 and 3 months, and a trend for higher NOX4 protein content at 1 month post‐injury.…”

“…Contribution to ROS production is also made by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. In rodents, protein content of NOX4, localized at the sarcoplasmic reticulum, increases following spinal cord injury, while NOX2 activity at the sarcolemma contributes to angiotensin II‐induced muscle atrophy (Liu et al, ; Kadoguchi et al, ). Finally, ROS production by xanthine oxidase (XO), during the final steps of purine degradation, increases during skeletal muscle atrophy in rodents (Kondo et al, ; Derbre et al, ).…”

Muscle wasting: A review of exercise, classical and non‐classical RAS axes

“…Ang‐II has two primary receptors: Ang‐II type 1 receptor (AT 1 R) and Ang‐II type 2 receptor (AT 2 R) . Ang‐II/AT 1 R signal transduction causes a pathological cascade resulting in increased reactive oxygen species (ROS), protein degradation, fibrosis and a decrease in protein synthesis within skeletal muscle . Ang‐II/AT 2 R signal transduction has been identified with the differentiation and regenerative processes of myoblasts, which indicates that the activation of AT 2 R may oppose the actions of AT 1 R activation …”