Possible Role of NADPH Oxidase 4 in Angiotensin II-Induced Muscle Wasting in Mice

Abstract

Background: Muscle wasting is a debilitating phenotype associated with chronic heart failure (CHF). We have previously demonstrated that angiotensin II (AII) directly induces muscle wasting in mice through the activation of NADPH oxidase (Nox). In this study, we tested the hypothesis that deficiency of NADPH oxidase 4 (Nox4), a major source of oxidative stress, ameliorates AII-induced muscle wasting through the regulation of redox balance.Methods and Results: Nox4 knockout (KO) and wild-type (WT) mice were used. At baseline, there were no differences in physical characteristics between the WT and KO mice. Saline (vehicle, V) or AII was infused via osmotic minipumps for 4 weeks, after which, the WT + AII mice showed significant increases in Nox activity and NOX4 protein compared with the WT + V mice, as well as decreases in body weight, gastrocnemius muscle weight, and myocyte cross-sectional area. These changes were significantly attenuated in the KO + AII mice (27 ± 1 vs. 31 ± 1 g, 385 ± 3 vs. 438 ± 13 mg, and 1,330 ± 30 vs. 2281 ± 150 μm2, respectively, all P < 0.05). The expression levels of phospho-Akt decreased, whereas those of muscle RING Finger-1 (MuRF-1) and MAFbx/atrogin-1 significantly increased in the WT + AII mice compared with the WT + V mice. Furthermore, nuclear factor erythroid-derived 2-like 2 (Nrf2) and the expression levels of Nrf2-regulated genes significantly decreased in the WT + AII mice compared with the WT + V mice. These changes were significantly attenuated in the KO + AII mice (P < 0.05).Conclusion: Nox4 deficiency attenuated AII-induced muscle wasting, partially through the regulation of Nrf2. The Nox4–Nrf2 axis may play an important role in the development of AII-induced muscle wasting.

SIRT1–NOX4 signaling axis regulates cancer cachexia

“…Of note, the NOX4 inhibitor GKT137831 is already in clinical trials for various diseases. Interestingly, Nox4 is also up-regulated in angiotensin II–induced muscle wasting, implying the possibility of a common pathway ( Kadoguchi et al, 2018 ) in multiple muscle disorders. Since other disorders such as muscular dystrophy also show increased muscle NF-κB or NOX4 activity ( Whitehead et al, 2010 ), GKT could be effective in treating muscle wasting induced by a variety of pathologies, a possibility that warrants further investigation.…”

Nox4 Knockout Does Not Prevent Diaphragm Atrophy, Contractile Dysfunction, or Mitochondrial Maladaptation in the Early Phase Post-Myocardial Infarction in Mice

“…The early phase post-MI is characterized by elevated circulating inflammatory cytokines and angiotensin II [12,13], which signal via reactive oxygen species (ROS) [3,14]. Excess ROS causes muscle weakness due to atrophy and contractile dysfunction [15,16] and impairs mitochondrial function [17].…”

“…A potential source of ROS downstream of inflammatory cytokines and angiotensin II is NADPH oxidase 4 (Nox4) [18,19]. Nox4, which localizes in the sarcoplasmic reticulum and mitochondria [20][21][22], causes skeletal muscle atrophy induced by angiotensin II infusion and pancreatic cancer [14,23], mediates contractile dysfunction in metastatic bone cancer [24], and promotes mitochondrial dysfunction [22]. In the early phase post-MI, the systemic environment is primed to activate Nox4 signaling [23,25,26].…”

TGF-β Regulates Collagen Type I Expression in Myoblasts and Myotubes via Transient Ctgf and Fgf-2 Expression

“…Furthermore, we show that TGF-β stimulates Nox4 and Id1 mRNA expression. These genes have been implied to play a role in muscle atrophy [34,35]. TGF-β has been shown to induce caspase 3 expression and DNA fragmentation in C2C12 cells [36].…”