title: Redox regulation of E3 ubiquitin ligases and their role in skeletal muscle atrophy.
abstract: Muscle atrophy is linked to reactive oxygen species (ROS) production during hindlimb-unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of our study was to determine the mechanism by which ROS cause muscle atrophy and its possible prevention by allopurinol, a well-known inhibitor of XO widely used in clinical practice, and indomethacin, a nonsteroidal anti-inflammatory drug. We studied the activation of p38 MAP Kinase and NF-?B pathways, and the expression of two E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFb) and Muscle RING Finger-1 (MuRF-1). Male Wistar rats (3 mold) conditioned by 14 days of hindlimb unloading (n=18), with or without the treatment, were compared with freely ambulating controls (n=18). After the experimental intervention, soleus muscles were removed, weighted and analyzed to determine oxidative stress and inflammatory parameters. We found that hindlimb unloading induced a significant increase in XO activity in plasma (39%, p=0.001) and in the protein expression of CuZnSOD and Catalase in skeletal muscle. Inhibitionof XO partially prevented protein carbonylation, both in plasma and in soleus muscle, in the unloaded animals. The most relevant new fact reported is that allopurinol prevents soleus muscle atrophy by ~20% after hindlimb unloading. Combining allopurinol and indomethacin we found a further prevention in the atrophy process. This is mediated by the inhibition of the p38 MAPK-MAFbx and NF-?B -MuRF-1 pathways. Our data point out the potential benefit of allopurinol and indomethacin administration for bedridden, astronauts, sarcopenic and cachexic patients.
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain. Electronic address: gloria.olaso@uv.es.
authors.forename: Gloria
authors.initials: G
authors.lastname: Olaso-Gonzalez
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ferrando
authors.affiliation: University of Rennes2 (UFR APS), Laboratory « Movement, Sport and health Sciences, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Derbre
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Salvador-Pascual
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Cabo
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Helios
authors.initials: H
authors.lastname: Pareja-Galeano
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Frederic
authors.initials: F
authors.lastname: Sabater-Pastor
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Mari Carmen
authors.initials: MC
authors.lastname: Gomez-Cabrera
authors.affiliation: University of Valencia (Faculty of Medicine), Department of Physiology, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Vina