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

Henríquez‐Olguín, Carlos; Boronat, Susanna; Cabello-Verrugio, Claudio; Jaimovich, Enrique; Hidalgo, Elena; Jensen, Thomas E.

doi:10.1089/ars.2018.7678

Cited by 45 publications

(38 citation statements)

References 410 publications

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“…Nox2 is a membrane oxidoreductase that produces ROS in response to skeletal muscle contractions [ 26 ] and stretch [ 27 ]. Extracellular ROS appear to communicate with neighboring myocytes, thus regulating contractile function [ 28 , 29 ], glucose uptake [ 30 , 31 ], pre-conditioning elevation of stress-protective proteins [ 32 ], metabolism [ 33 ], and gene expression [ 34 ]. However, the assembly of the Nox2 complex dramatically rises with Duchenne muscular dystrophy [ 35 ] and Type II diabetes [ 36 ], contributing to pathology.…”

Section: Discussionmentioning

confidence: 99%

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

Lawler

Hord

Ryan

et al. 2021

IJMS

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Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

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Section: Discussionmentioning

confidence: 99%

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

Lawler

Hord

Ryan

et al. 2021

IJMS

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“…3 indicate that oxidation of the mitochondrial isoform (Prx3) occurred with contractile activity in addition to the cytosolic-located isoforms (Prx1 and 2). Recent studies have implicated NADPH oxidase 2 as the major source of contraction-induced ROS generation [ 46 , 50 , 51 ], but older [ 6 ] and some longer duration studies [ 51 ], suggested mitochondria might also be an important source of ROS during muscle contractions. While the source of the ROS that induced oxidation of Prx3 in this model is unclear, the data in Fig.…”

Section: Discussionmentioning

confidence: 99%

2-Cys peroxiredoxin oxidation in response to hydrogen peroxide and contractile activity in skeletal muscle: A novel insight into exercise-induced redox signalling?

Stretton¹,

Pugh

McArdle³

et al. 2020

Free Radical Biology and Medicine

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Skeletal muscle generates superoxide during contractions which is rapidly converted to H 2 O 2 . This molecule has been proposed to activate signalling pathways and transcription factors that regulate key adaptive responses to exercise but the concentration of H 2 O 2 required to oxidise and activate key signalling proteins in vitro is much higher than the intracellular concentration in muscle fibers following exercise. We hypothesised that Peroxiredoxins (Prx), which reacts with H 2 O 2 at the low intracellular concentrations found in muscle, would be rapidly oxidised in contracting muscle and hence potentially transmit oxidising equivalents to downstream signalling proteins as a method for their oxidation and activation. The aim of this study was to characterise the effects of muscle contractile activity on the oxidation of Prx1, 2 and 3 and determine if these were affected by aging. Prx1, 2 and 3 were all rapidly and reversibly oxidised following treatment with low micromolar concentrations of H 2 O 2 in C2C12 myotubes and also in isolated mature flexor digitalis brevis fibers from adult mice following a protocol of repeated isometric contractions. Significant oxidation of Prx2 was seen within 1 min (i.e. after 12 contractions), whereas significant oxidation was seen after 2 min for Prx1 and 3. In muscle fibers from old mice, Prx2 oxidation was significantly attenuated following contractile activity. Thus we show for the first time that Prx are rapidly and reversibly oxidised in response to contractile activity in skeletal muscle and hypothesise that these proteins act as effectors of muscle redox signalling pathways which are key to adaptations to exercise that are attenuated during aging.

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“…Skeletal muscle has several sources of ROS, but mitochondria [ 14 ], NADPH oxidase enzymes (NOX/DUOX) [ 15 ], and xanthine oxidase (XO) [ 16 ] seem to be the three most relevant during exercise. While O 2 •− are generated by mitochondria and XO as a secondary sub-product of oxidative phosphorylation and purine metabolism, respectively, NAPDH oxidase enzymes are exclusively dedicated to generating superoxide and H 2 O 2 [ 17 , 18 ] ( Figure 1 ).…”

Section: Main Sources Of Ros In Skeletal Muscle During Contractionmentioning

confidence: 99%

“…Activation of the NOX2-p22phox complex requires the translocation of cytosolic factors such as p47phox, p67phox, and p40phox to the membrane. Phosphorylation of p47phox induces a change in its conformation that enables it to bind p22phox, thus promoting the interaction of the other cytosolic factors with NOX2 [ 18 ]. Additionally, p22phox is a functional binding partner of NOX4, but its activity seems to be mainly dependent on its expression level, as well as the partial oxygen pressure [ 17 , 29 , 35 ].…”

Section: Main Sources Of Ros In Skeletal Muscle During Contractionmentioning

confidence: 99%

Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle

et al. 2021

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Physical exercise represents a major challenge to whole-body homeostasis, provoking acute and adaptative responses at the cellular and systemic levels. Different sources of reactive oxygen species (ROS) have been described in skeletal muscle (e.g., NADPH oxidases, xanthine oxidase, and mitochondria) and are closely related to the physiological changes induced by physical exercise through the modulation of several signaling pathways. Many signaling pathways that are regulated by exercise-induced ROS generation, such as adenosine monophosphate-activated protein kinase (AMPK), mitogen activated protein kinase (MAPK), nuclear respiratory factor2 (NRF2), and PGC-1α are involved in skeletal muscle responses to physical exercise, such as increased glucose uptake, mitochondriogenesis, and hypertrophy, among others. Most of these adaptations are blunted by antioxidants, revealing the crucial role played by ROS during and after physical exercise. When ROS generation is either insufficient or exacerbated, ROS-mediated signaling is disrupted, as well as physical exercise adaptations. Thus, an understanding the limit between “ROS that can promote beneficial effects” and “ROS that can promote harmful effects” is a challenging question in exercise biology. The identification of new mediators that cause reductive stress and thereby disrupt exercise-stimulated ROS signaling is a trending on this topic and are covered in this current review.

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

Cited by 45 publications

References 410 publications

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

2-Cys peroxiredoxin oxidation in response to hydrogen peroxide and contractile activity in skeletal muscle: A novel insight into exercise-induced redox signalling?

Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle

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