title: NADPH oxidase hyperactivity induces plantaris atrophy in heart failure rats.
abstract: BACKGROUND
  Skeletal muscle wasting is associated with poor prognosis and increased mortality in heart failure (HF) patients. Glycolytic muscles are more susceptible to catabolic wasting than oxidative ones. This is particularly important in HF since glycolytic muscle wasting is associated with increased levels of reactive oxygen species (ROS). However, the main ROS sources involved in muscle redox imbalance in HF have not been characterized. Therefore, we hypothesized that NADPH oxidases would be hyperactivated in the plantaris muscle of infarcted rats, contributing to oxidative stress and hyperactivation of the ubiquitin-proteasome system (UPS), ultimately leading to atrophy.
  
  
  METHODS
  Rats were submitted to myocardial infarction (MI) or Sham surgery. Four weeks after surgery, MI and Sham groups underwent eight weeks of treatment with apocynin, a NADPH oxidase inhibitor, or placebo. NADPH oxidase activity, oxidative stress markers, NF-κB activity, p38 MAPK phosphorylation, mRNA and sarcolemmal protein levels of NADPH oxidase components, UPS activation and fiber cross-sectional area were assessed in the plantaris muscle.
  
  
  RESULTS
  The plantaris of MI rats displayed atrophy associated with increased Nox2 mRNA and sarcolemmal protein levels, NADPH oxidase activity, ROS production, lipid hydroperoxides levels, NF-κB activity, p38 MAPK phosphorylation and UPS activation. NADPH oxidase inhibition by apocynin prevented MI-induced skeletal muscle atrophy by reducing ROS production, NF-κB hyperactivation, p38 MAPK phosphorylation and proteasomal hyperactivity.
  
  
  CONCLUSIONS
  Our data provide evidence for NADPH oxidase hyperactivation as an important source of ROS production leading to plantaris atrophy in heart failure rats, suggesting that this enzyme complex plays key role in skeletal muscle wasting in HF.
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Brazil.
authors.forename: Luiz R G
authors.initials: LR
authors.lastname: Bechara
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Brazil; K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Jose B N
authors.initials: JB
authors.lastname: Moreira
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Brazil.
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Jannig
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Brazil.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Voltarelli
authors.affiliation: Heart Institute, Faculty of Medicine, University of Sao Paulo, Brazil.
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Dourado
authors.affiliation: Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Brazil.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Vasconcelos
authors.affiliation: Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Brazil.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Scavone
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Brazil.
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Ramires
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Brazil. Electronic address: pcbrum@usp.br.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009133:Muscular Atrophy / Q000201:enzymology* / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Atrophy; Heart failure; NADPH oxidase; Oxidative stress; Skeletal muscle