Inhibition of xanthine oxidase by allopurinol prevents skeletal muscle atrophy: role of p38 MAPKinase and E3 ubiquitin ligases.
Alterations in muscle play an important role in common diseases and conditions. Reactive oxygen species (ROS) are generated during hindlimb unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of this study was to determine the mechanism by which XO activation causes unloading-induced muscle atrophy in rats, and its possible prevention by allopurinol, a well-known inhibitor of this enzyme. For this purpose we studied one of the main redox sensitive signalling cascades involved in skeletal muscle atrophy i.e. p38 MAPKinase, and the expression of two well known muscle specific E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFbx; also known as atrogin-1) and Muscle RING (Really Interesting New Gene) Finger-1 (MuRF-1). We found that hindlimb unloading induced a significant increase in XO activity and in the protein expression of the antioxidant enzymes CuZnSOD and Catalase in skeletal muscle. The most relevant new fact reported in this paper is that inhibition of XO with allopurinol, a drug widely used in clinical practice, prevents soleus muscle atrophy by ~20% after hindlimb unloading. This was associated with the inhibition of the p38 MAPK-MAFbx pathway. Our data suggest that XO was involved in the loss of muscle mass via the activation of the p38MAPK-MAFbx pathway in unloaded muscle atrophy. Thus, allopurinol may have clinical benefits to combat skeletal muscle atrophy in bedridden, astronauts, sarcopenic, and cachexic patients.
Laboratory Movement Sport and Health Sciences, University Rennes 2-ENS Cachan, Rennes, France.
Frederic
F
Derbre
Beatriz
B
Ferrando
Mari Carmen
MC
Gomez-Cabrera
Fabian
F
Sanchis-Gomar
Vladimir E
VE
Martinez-Bello
Gloria
G
Olaso-Gonzalez
Ana
A
Diaz
Arlette
A
Gratas-Delamarche
Miguel
M
Cerda
Jose
J
Viña
D000493:Allopurinol / Q000008:administration & dosage*; D000818:Animals; D004789:Enzyme Activation; D019417:Hindlimb Suspension; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000517:prevention & control*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism* / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D000493:Allopurinol; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases