Regulation of NADPH oxidases in skeletal muscle

Abstract

The only known function of NAD(P)H oxidases is to produce reactive oxygen species (ROS). Skeletal muscles express three isoforms of NAD(P)H oxidases (Nox1, Nox2, and Nox4) that have been identified as critical modulators of redox homeostasis. Nox2 acts as the main source of skeletal muscle ROS during contractions, participates insulin signaling and glucose transport, and mediates the myocyte response to osmotic stress. Nox2 and Nox4 contribute to skeletal muscle abnormalities elicited by angiotensin II, muscular dystrophy, heart failure, and high fat diet. Our review addresses the expression and regulation of NAD(P)H oxidases with emphasis on aspects that are relevant to skeletal muscle. We also summarize: i) the most widely used NAD(P)H oxidases activity assays and inhibitors, and ii) studies that have defined Nox enzymes as protagonists of skeletal muscle redox homeostasis in a variety of health and disease conditions.

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

“…Thus, mitochondrial ROS are a crucial component of the signaling pathway that culminates in diaphragm dysfunction in CHF. A plausible mechanism that reconciles findings in CHF is a cross-talk between Nox and mitochondria through ROS-induced ROS release [156,127,153,157]. …”

“…The main sources of ROS in diaphragm are NAD(P)H oxidases and mitochondria [151–153]. CHF heightens diaphragm mRNA and protein levels of Nox2 subunits of NAD(P)H oxidase.…”

“…CHF heightens diaphragm mRNA and protein levels of Nox2 subunits of NAD(P)H oxidase. Phosphorylation of the Nox2 subunit p47 phox is a critical step for enzyme activation and ROS production [154,153], and CHF increases phosphorylation of p47 phox in the diaphragm [83]. Mice deficient in p47 phox , which lack Nox2 activity [155], are protected from CHF-induced increase in diaphragm ROS emission and impairments in isometric and isotonic contractile properties [83].…”

Diaphragm Abnormalities in Patients with End-Stage Heart Failure: NADPH Oxidase Upregulation and Protein Oxidation

“…An important source of ROS in the diaphragm is the Nox2 isoform of NAD(P)H oxidase (Pal et al, 2013; Loehr et al, 2014; Bost et al, 2015). A functionally assembled Nox2 enzyme complex consists of several subunits (Nox2, p22 phox , p67 phox , p40 phox , Rac1/2, and p47 phox ), and enzyme activation requires p47 phox phosphorylation (Javesghani et al, 2002; Lassègue et al, 2012; Pal et al, 2013; Ferreira and Laitano, 2016). Diaphragm p47 phox phosphorylation is increased in mice with HF, and genetic deletion of p47 phox prevents excess ROS release and contractile dysfunction in diaphragm of mice with HF (Ahn et al, 2015).…”

Impact of single anaerobic exercise on delayed activation of endothelial xanthine oxidase in men and women

“…According to studies conducted among humans and animal models, the main source of ROS in high-intensity exercises is catalyzed reactions through Nox2 and Nox4 isoforms of NAD(P) H oxidase, located respectively in the sarcolemma and sarcoplasmic reticulum of myocytes, as well as the NAD(P)H oxidase of microvascular endothelial cells, muscle cells and phagocytes [1,[7][8][9][10][11]. In these reactions, the following develop: superoxide anion (O ·− 2 ) and hydrogen peroxide (H 2 O 2 ), belonging to ROS [1].…”