title: NOX2 Inhibition Impairs Early Muscle Gene Expression Induced by a Single Exercise Bout.
abstract: Reactive oxygen species (ROS) participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2) in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg) or vehicle for 3 days, were swim-exercised for 60 min. Phospho-p47(phox) levels were significantly upregulated by exercise in flexor digitorum brevis (FDB). Moreover, exercise significantly increased NOX2 complex assembly (p47(phox)-gp91(phox) interaction) demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx), citrate synthase (CS), mitochondrial transcription factor A (tfam) and interleukin-6 (IL-I6) in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-κB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p < 0.001). These results were corroborated using gp91-dstat in an in vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise.
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de ChileSantiago, Chile; Laboratory of Exercise Sciences, Clínica MEDSSantiago, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Henríquez-Olguín
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Alexis
authors.initials: A
authors.lastname: Díaz-Vegas
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Yildy
authors.initials: Y
authors.lastname: Utreras-Mendoza
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Campos
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Arias-Calderón
authors.affiliation: Facultad de Odontología, Institute for Research in Dental Sciences, Universidad de Chile Santiago, Chile.
authors.forename: Paola
authors.initials: P
authors.lastname: Llanos
authors.affiliation: Facultad de Medicina, School of Medical Technology, Universidad de Chile Santiago, Chile.
authors.forename: Ariel
authors.initials: A
authors.lastname: Contreras-Ferrat
authors.affiliation: Facultad de Medicina, School of Medical Technology, Universidad de Chile Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Espinosa
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Altamirano
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Jaimovich
authors.affiliation: Facultad de Medicina, Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Universidad de Chile Santiago, Chile.
authors.forename: Denisse M
authors.initials: DM
authors.lastname: Valladares
keywords: IL-6; NADPH oxidase; antioxidant defense; muscle adaptation; reactive oxygen species; redox signaling